International Journal of

Molecular Sciences

Review
The Role of Obesity and Diabetes in Dementia
Ashley Selman 1 , Scott Burns 1 , Arubala P. Reddy 2 , John Culberson 3 and P. Hemachandra Reddy 1,2,4,5,6,7, *

1 Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
2 Nutritional Sciences Department, College Human Sciences, Texas Tech University, Lubbock, TX 79409, USA
3 Department of Family Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
4 Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center,
Lubbock, TX 79430, USA
5 Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
6 Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences
Center, Lubbock, TX 79430, USA
7 Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center,
Lubbock, TX 79430, USA
* Correspondence: hemachandra.reddy@ttuhsc.edu; Tel.: +1-806-743-3194

Abstract: Chronic conditions such as obesity, diabetes, and dementia are increasing in the United
States (US) population. Knowledge of these chronic conditions, preventative measures, and proper
management tactics is important and critical to preventing disease. The overlap between obesity,
diabetes, and dementia is becoming further elucidated. These conditions share a similar origin
through the components of increasing age, gender, genetic and epigenetic predispositions, depression,
and a high-fat Western diet (WD) that all contribute to the inflammatory state associated with the
development of obesity, diabetes, and dementia. This inflammatory state leads to the dysregulation
of food intake and insulin resistance. Obesity is often the cornerstone that leads to the development
of diabetes and, subsequently, in the case of type 2 diabetes mellitus (T2DM), progression to “type 3
diabetes mellitus (T3DM)”. Obesity and depression are closely associated with diabetes. However,
dementia can be avoided with lifestyle modifications, by switching to a plant-based diet (e.g., a
Citation: Selman, A.; Burns, S.; Mediterranean diet (MD)), and increasing physical activity. Diet and exercise are not the only treat-
Reddy, A.P.; Culberson, J.; Reddy, P.H. ment options. There are several surgical and pharmacological interventions available for prevention.
The Role of Obesity and Diabetes in Current and future research within each of these fields is warranted and offers the chance for new
Dementia. Int. J. Mol. Sci. 2022, 23, treatment options and a better understanding of the pathogenesis of each condition.
9267. https://doi.org/10.3390/
ijms23169267
Keywords: Western diet; type 2 diabetes; dementia; obesity; depression; Mediterranean diet
Academic Editor: Jean-François Tanti

Received: 23 July 2022

Accepted: 15 August 2022
1. Introduction
Published: 17 August 2022
Chronic diseases have become a serious problem in modern society and two of the
Publisher’s Note: MDPI stays neutral most prominent conditions, diabetes mellitus and dementia, are closely linked to obesity.
with regard to jurisdictional claims in
The Centers for Disease Control and Prevention (CDC) deems the steady rise in obesity
published maps and institutional affil-
within the United States (US) over the past few decades as an epidemic (Table 1) [1]. In
iations.
2017, 4 million people died due to obesity and obesity-related complications, with 41.9% of
the US population being deemed obese [2]. Current research links the obesity epidemic
to multiple detrimental chronic conditions (e.g., diabetes, heart disease, dementia) that
Copyright: © 2022 by the authors.
have lowered the quality and length of life for countless individuals (Figure 1) [3]. As of
Licensee MDPI, Basel, Switzerland. 2020, 55 million people have been diagnosed with dementia and by 2050 this number is
This article is an open access article expected to rise to 139 million, likely due to the steady rise in obesity prevalence [3–5].
distributed under the terms and This article examines the factors surrounding the development of obesity and the role that
conditions of the Creative Commons obesity plays in perpetuating the prevalence of diabetes and dementia.
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

Int. J. Mol. Sci. 2022, 23, 9267. https://doi.org/10.3390/ijms23169267 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022, 23, 9267 2 of 25

Table 1. Rising incidence of obesity and diabetes mellitus.

Year Range Obesity Prevalence Percentage Diabetes Mellitus Prevalence Percentage

1988–1994 20.2 8.8
1999–2002 27.6 10.8
2011–2014 34.25 12.9
2015–2018 40.45 14.4

Figure 1. Long-term consequences of obesity and diabetes mellitus. Obesity is heavily linked as a
causative agent of diabetes mellitus, especially type 2. Diabetes leads to the development of coro-
nary artery disease (CAD), diabetic nephropathy, peripheral vascular disease, diabetic neuropathy,
cardiovascular accident (stroke), and dementia.

The rise in the incidence of obesity and diabetes leads to a corresponding increase in
the risk of developing dementia. The table above was constructed utilizing data from the
Centers for Disease Control and Prevention (CDC) with these parameters: (1) adults aged
20 years and older, (2) obesity prevalence calculated based upon only adults classified as
having “obesity”, (3) diabetes mellitus prevalence calculated using data encompassing type
1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) as well as physician- and
non-physician-diagnosed diabetes [5,6].
Obesity is defined as an “abnormal or excessive fat accumulation that presents a risk to
health” and a body mass index (BMI) over 30. The term “overweight” is defined similarly,
but with a BMI over 25. Obesity is most frequently caused by consuming an excess number
Int. J. Mol. Sci. 2022, 23, 9267 3 of 25

of calories than is required for basal metabolic activities and physical exertion. However, all
people are not created equal in this epidemic [2]. Some populations are disproportionately
affected due to an interplay of several factors, such as age, gender, genetic and epigenetic
factors, and the social determinants of health [1]. Many of these elements work concurrently
to cause obesity, which in turn further bolsters the incidence of diabetes and dementia
(Figure 2).

Figure 2. Causes of obesity and its association with diabetes mellitus and dementia. Obesity is a
multifactorial condition, determined by not just an imbalance of caloric intake and usage, but also
by several other factors. The main determining factors are age, gender, diet, genetic predisposition,
epigenetic impact, depression, and socioeconomic status.

Extensive research cites several hypotheses linking obesity with the chronic conditions
of diabetes. The most prominent and current of these hypotheses are the: (1) inflammation
hypothesis, (2) lipid overflow hypothesis, and (3) adipokine hypothesis [6]. These hy-
potheses all center around the concept of increased insulin resistance, cytokines and other
inflammatory mediators, lipid storage, and how obesity stimulates diabetes at the molecu-
lar level [7–10]. These cellular pathologies translate into the classical clinical presentation
of hyperglycemia, which leads to polyuria, polydipsia, nocturia, and blurred vision [11].
Chronically elevated blood glucose levels lead to vascular damage, which causes further
complications, such as coronary artery disease (CAD), peripheral neuropathy, stroke, and
chronic kidney disease (Figure 1).
Int. J. Mol. Sci. 2022, 23, 9267 4 of 25

Diabetes can be subdivided into four categories: type 1, type 2, gestational, and specific
cause-based types [12] (Figure 3). Type 1 diabetes is classified as an autoimmune disorder
in which the body destroys insulin-producing pancreatic beta cells leading to an insulin
deficiency, which also includes latent autoimmune diabetes in adulthood. Type 2 diabetes
is the most common and is due to a combination of insulin resistance and a failure of
pancreatic beta cells to secrete insulin [12,13]. “Type 3 diabetes” is a subset of type 2 and
has been dubbed “brain diabetes” due to the strong correlation between type 2 diabetes
and Alzheimer’s disease [13–16]. Gestational diabetes develops in pregnant women with
no previous signs of diabetes who develop elevated glucose levels during the second or
third trimester that typically resolves after giving birth. There are other types of diabetes
linked to specific causes such as: (1) monogenic diabetes syndromes (e.g., neonatal diabetes,
maturity-onset diabetes), (2) exocrine pancreas affecting disorders (e.g., cystic fibrosis,
pancreatitis), and (3) chemical-induced diabetes (e.g., glucocorticoids) [11,12].

Figure 3. Classifications of diabetes mellitus and dementias. Figure illustrates the four types of
diabetes mellitus and the relationship between type 2 diabetes mellitus (T2DM) and dementia,
specifically Alzheimer’s disease (AD). T2DM has a close link to AD, leading to an umbrella type of
diabetes known as “type 3 diabetes mellitus” (T3DM).

The chain reaction set off by obesity can be seen in the brain as dementia and other
mental disorders like AD. Dementia is the overarching term to describe a group of neu-
rological conditions that lead to a progressive decline in cognitive function and impairs
the ability to reason and think, manage emotions, and can lead to a shift in personality.
There are five common types of dementia: (1) AD, (2) frontotemporal dementia (FTD),
Int. J. Mol. Sci. 2022, 23, 9267 5 of 25

(3) Lewy body dementia, (4) vascular dementia, and (5) mixed dementia [17] (Figure 3).
Those suffering from type 2 diabetes have a 19% higher chance of specifically developing
the vascular dementia form [17]. Obesity’s strong link to type 2 diabetes is what connects
it to a decreased mental state. Type 2 diabetes increases the risk of developing a cogni-
tive disorder by 60%, with a correlation so strong it has become another type of diabetes:
type 3 [13,15–17].
This article investigates the role that obesity plays in perpetuating the prevalence of
diabetes and dementia and the factors that contribute to the development of obesity in the
population. In line with this goal, the following are discussed: (1) specific factors that affect
the obesity rate in populations, including age, gender, genetics and epigenetics, nutrition,
and the pertinence of socioeconomic factors, (2) the relationship between obesity, diabetes,
and dementia, with a particular examination of the role of inflammation, (3) the impact of
diabetes on dementia, (4) the current status of research on obesity, diabetes, and dementia,
(5) research directions in the area of obesity and its role in diabetes and dementia, and
(6) the current therapeutics (e.g., medications, diet, exercise) for diabetes and dementia.

2. Factors Affecting the Development of Obesity

2.1. Age and Obesity
Age and obesity have a convoluted and cyclic relationship. Individuals are more prone
to experience an increase in central obesity as they age due to the decline in metabolic
function [18]. Centralized obesity is a major contributor to key agents of oxidative stress-
induced insulin resistance and metabolic syndrome [18]. The surgical removal of this
visceral fat in mice counteracted the insulin resistance and occurrence of metabolic syn-
drome [18]. Moreover, obese individuals also have higher levels of inflammatory cytokines,
which are shown to accelerate the aging process, creating a perpetually damaging cycle [19].
This inflammatory environment is created in part by the cytokines: tumor necrosis factor
alpha (TNF-α) and interleukin 6 (IL-6), which are biomarkers for aging and are secreted
by both immune cells and white adipose tissue (WAT). Both levels of these inflammatory
cytokines increase with age [20]. Within the WAT, the stromal vascular fraction (SVF),
home to the M2-type macrophages and T-cells, secretes IL-6 [21]. This cytokine affects the
metabolism, which increases the amount of the appetite-quelling hormone leptin and helps
increase hepatic insulin resistance through the release of free fatty acids [19].
Age is believed to be correlated with two other important molecules—adiponectin
and leptin. These two are thought to be impacted by the central redistribution and increase
of WAT, while also playing a role in regulating metabolism (Figure 4). Adiponectin levels
positively correlated with age, and in the Li et al. (2021) mice study, adiponectin proved
key in determining “healthspan” and lifespan [22]. This adipokine is unique in that it
has an antagonistic impact on obesity. Although it is secreted by adipocytes, adiponectin
increases the rate of lipid metabolism and also has insulin-sensitizing and anti-inflammatory
effects [19]. Obesity lowers levels of adiponectin, furthering the perpetual inflammatory
state and insulin resistance [18].
Leptin is another adipokine that combats obesity. Leptin lowers appetite by com-
municating with the satiety centers of the brain and stimulates fat oxidation [23]. Obese
individuals tend to have increased levels of leptin; however, while this might seem to be
beneficial, it is not, because it leads to leptin resistance [24,25]. Research indicates that
individual leptin levels increase with age, and although evidence shows leptin protects
against cognitive decline, this only seems to hold true for those with a healthy BMI, likely
due to leptin resistance [26]. Women seem to benefit more from the protective effects of
high leptin levels. The development of neurodegenerative disorders, particularly AD, are
associated with low leptin levels [25,26].
Int. J. Mol. Sci. 2022, 23, 9267 6 of 25

Figure 4. Genetic predisposition for development of obesity. The predisposition for the development
of obesity is dictated by several genes, both nuclear and mitochondrial. The nuclear genes insulin-
induced gene 2 (INSIG2), proprotein convertase subtilisin/kexin type 1 (PCKS1), and peroxisome
proliferator-activated receptor gamma (PPARG) play a role in metabolism regulation. Mutations or
single nuclear polymorphisms (SNPs) cause the dysregulation of these genes and thus awry metabolic
function that can stimulate the development of obesity.

2.2. Gender and Obesity

Gender is a major factor in the development of obesity. Most women are twice as
likely to become overweight or obese compared to men. Women also have a far greater
chance of suffering from obesity-related complications with double the mortality rate [27].
A study that compared 1178 South Asian adults found a significantly higher rate of obesity
among female participants, with women being 2.5 times more likely to develop centralized
obesity compared to their male counterparts [28]. Women are disproportionately affected
by obesity and obesity-related complications due to the impact of their emotional state
(e.g., negative emotions correlate with stress eating), hormones, and degree of physical
health. States of emotional flux or distress are associated with an increase in caloric intake
in women. Research indicates these negative emotional states trigger higher incidences
of food cravings in both males and females [29]. However, the reported foods craved by
females are categorized as “sweet” and are typically more calorically dense (e.g., chocolate,
ice cream), whereas males in the study craved more protein rich “savory” foods (i.e., meat).
At the biological level, hormones offer another potential explanation for the discrepancy in
obesity rates between men and women. Androgens (i.e., testosterone) tend to reduce the
development of diabetes and obesity in men [30]. Estrogen, the predominate hormone in
females, is linked to a reduction in appetite and inflammation in women. Postmenopausal
women showed an increased propensity to gain weight following a decrease in estrogen
levels [30]. The clinical determinants, including pregnancy, hormonal birth control (chronic
contraceptive use is associated with a higher body weight and adiposity), menopause,
and polycystic ovary syndrome (PCOS) also contribute to the variance between men and
women. In addition to generally having more pre-dispositional factors, it is important to
note that women also have a higher rate of mortality due to obesity-related complications
because they have a higher risk of developing these complications [27]. Dementia is one
such complication, and given that JAMA reports that two-thirds of the adults diagnosed
with AD are women, obesity is a pivotal modifiable risk factor [5].
Int. J. Mol. Sci. 2022, 23, 9267 7 of 25

2.3. Genetic Factors Impacting the Development of Obesity

Humans are a compilation of genes and behaviors; therefore, it is easy to understand
why genetic elements impact the likelihood of becoming obese. Despite the large genetic
pool that contributes to the development of obesity, this article only examines three genes
commonly associated with obesity with a strong subsequent link to diabetes: the insulin-
induced gene 2 (INSIG2), proprotein convertase subtilisin/kexin type 1 (PCKS1), and
peroxisome proliferator-activated receptor gamma (PPARG) genes [31,32] (Figure 4). Other
genes that can predispose individuals to obesity include the fat mass and obesity-associated
(FTO) gene, leptin receptor (LEPR), and melanocortin-4 receptor (MCR4) [32,33].
The INSIG2 gene, found on chromosome 2q14.2, is an endoplasmic reticulum protein
that inhibits sterol response element-binding protein (SREBP) activation. This prevents the
binding of SREBPs to the SCREBP cleavage-activating proteins (SCAP), which blocks SREBP
movement to the Golgi and ultimately impacts the regulation of cholesterol and fatty acid
synthesis. There are two control points that lead to the activation of INSIG2: (1) increased
high-cholesterol levels and (2) insulin induction. The single nuclear polymorphism (SNP)
rs7566605 of INSIG2 is associated with INSIG2 dysregulation and a 40% increased risk of
developing obesity [34,35] (Figure 4).
Another gene, PCKS1, is located on chromosome 5q15.21 and codes for the proteolytic
prohormone convertase PC1/3, and controls the cleavage and activation of metabolic
regulating precursors (e.g., proopiomelanocortin, proinsulin, proglucagon, proghrelin) [29].
The prohormone convertase (PC1/3) helps regulate glucose homeostasis and appetite,
which predisposes individuals with mutations in the PCSK1 gene to obesity and diabetes.
Specifically, the N221D allele has a strong tie to diabetes due to its deleterious effect on
insulin sensitivity and oral glucose tolerance, while increasing the circulating proinsulin
(Figure 4). N221D is also correlated with an increased risk for pediatric obesity [36].
A protein-coding gene, PPARG, is a gene that, once translated, yields a nuclear ligand-
dependent transcription factor that is found in adipocytes. The PPARG gene serves as a
key metabolic regulator that aids in controlling adipogenesis, lipid storage and metabolism,
thermogenesis, and insulin sensitivity [37]. This gene is associated with the “browning”
of WAT into brown adipose tissue (BAT), a special type of adipose tissue that is credited
with regulating thermogenesis due to an upregulated amount of the uncoupling protein 1
(UPC1) gene. BAT, in essence, is a type of fat that “burns” itself off to maintain thermogenic
homeostasis [38]. The importance of this gene in multiple metabolic processes allows it
to be detrimental in the case of certain variants, such as the SNP Pro12Ala that leads to
an increased risk of developing both obesity and type 2 diabetes [37] (Figure 4). Studies
indicate that individuals who possess the Ala12 allele consistently maintain a steady body
weight and insulin sensitivity. In contrast, individuals who possess Pro12Ala mutated
allele exhibit a greater difficulty with weight loss [39].

2.4. Epigenetics and Predisposition for Obesity

The genetic code lays the foundation for an increased tendency towards obesity, but
the epigenetic alterations made to the genome are fascinatingly pivotal pieces of the puzzle.
Epigenetics can be defined as heritable alterations that impact gene expression and function,
but do not change the actual genetic code. This process occurs through methylating and
acetylating the deoxyribonucleic acid (DNA) or histones or alteration of the micro-RNA
(miRNA). Methylation generally compacts and silences DNA, while acetylation generally
activates DNA. miRNA serves another means of lowering DNA expression by acting as a
blockade and preventing any enzymatic activity [40]. Epigenetics affects every aspect of
one’s health and can be altered in a variety of ways, through maternal actions during and
prior to the gestational period and later through diet and exercise. Therefore, epigenetics
can be a two-way street—some alterations may predispose individuals to obesity, but
obesity and the lifestyle that stimulates it can also cause these genomic changes and further
perpetuate obesity.
Int. J. Mol. Sci. 2022, 23, 9267 8 of 25

The maternal state of health heavily dictates embryonic development and the health
of a newborn. However, several studies suggest that the impact of a mother’s health
and lifestyle conditions can have long-lasting effects and can predispose their child to
obesity. Most interestingly, this is illustrated in a small study that compared the offspring
of obese mothers who underwent gastric bypass surgery [41]. The children born prior
to the mother’s gastric bypass surgery had greater obesity attributes than their siblings
born after the surgery and maternal weight loss. The study found differences in the
methylation profiles when comparing the metabolic and insulin-regulating genes [41].
Other examinations reveal key areas of the genome responsible for a rise in adiposity. The
retinoid X receptor alpha gene (RXRα), which is PPARG’s heterodimeric partner, works in
the adipocyte to regulate adipogenesis and metabolic processes [37]. The methylation of
RXRα at birth increases the risk of obesity, which explains about 26% of the variation in
childhood obesity.
The insulin-like growth factor 2 (IGF2) also plays a role in embryonic development.
This gene is classified as an “imprinted” gene from a paternally derived allele, with the
maternal allele silenced. The methylation of IGF2 at H19 is associated with an increased
risk of early-onset obesity in children and higher circulating levels of the protein encoded
by IGF2 in adults [42]. Although this is a paternally derived allele, maternal actions dictate
the status and impact of methylation. Maternal breastfeeding may blunt the effects of H19
methylation [42]. Regular maternal exercise during the gestational period may also blunt
the levels of methylation found on the IGF2 gene [43].
Diet and nutrition are key mediators of obesity and can also incite changes in epigenetic
factors. Caloric surplus is the biggest cause of obesity, but particular types of diets are more
prone to inducing a greater risk of obesity. A high-fat diet (HFD), for example, is linked to
altering the epigenome and raising the risk of obesity. A clinical trial utilizing an HFD for
five days found an increase in the methylation of PPARG [44]. Other notable epigenomic
changes occur with an increased expression of histone deacetylases (HDAC): HDAC5,
HDAC8, and HDAC9. These enzymes alter the expression of the genes responsible for
metabolism and appetite regulation, leading to an increased propensity for obesity [44].

2.5. Socioeconomic Status and Obesity

Obesity is a socioeconomic problem as well as a biological problem. Those of a lower
socioeconomic status are disproportionately affected by the obesity epidemic due to a
lower quality diet and lack of resources (e.g., access to workout facilities and supermarkets,
proper health/nutrition education, time) [38]. Minority groups are hit the hardest by
these disparities, especially within rural areas. Healthier food options tend to be more
expensive than processed, calorie-dense food options. These cheaper options are also easier
to access than more nutritious options due to the lack of supermarket availability in lower
socioeconomic populations. The use of government assistance food stamp programs also
has a correlation with a higher BMI due to the high sugar and fat content of the food offered.
Along with less access to supermarkets, minority groups also have less access to physical
activity centers (e.g., gyms). This works detrimentally in tandem with the decline in safe
and well-maintained outdoor recreational spaces and the decrease in walking as a form of
transportation [45].

3. Diabetes and Obesity

The previously discussed factors all perpetuate obesity and thus diabetes; however,
inflammation is the key factor and mediator of both obesity and diabetes. Although a state
of caloric surplus promotes an inflammatory state, studies indicate that the immune system
plays a role as well through the following: (1) central nervous system (CNS) inflammation,
(2) TLR activation, and (3) certain gut microbiota [46]. This inflammatory response mediates
various components of the immune system, most notably macrophages and T-cells. There
are currently three working hypotheses on how adipocytes are stimulated within the
immune system: (1) adipocytes secrete cytokines that recruit monocytes (become M1
Int. J. Mol. Sci. 2022, 23, 9267 9 of 25

macrophages) and T-cells, (2) an HFD stimulates the toll-like receptor 4 (TLR4) and mounts
an immune response, and (3) adipocyte death recruits macrophages to clean up necrotic
cells [46,47]. This section specifically discusses the role of NF-kB and related pathways,
CNS control and the impact of inflammation, and the types of diabetes and their subsequent
relationship to inflammation and dementia (Figure 5).

Figure 5. Role of NF-κB activation in the development of obesity, diabetes mellitus, and dementia.
Activation of NF-κB is a nuclear transcription factor linked to the ignition of inflammation via
the release of inflammatory cytokines (e.g., IL-1, IL-1β) that leads to the dysregulation of several
pathways throughout the body. One noteworthy impact of this inflammation is the transformation
of brown adipose tissue (BAT) to white adipose tissue (WAT). High WAT content is a hallmark of
obesity, and from obesity, diabetes and dementia develop. Note that inflammation lends itself to the
direct development of both diabetes and dementia.

3.1. NF-κβ and the Impact of the Inflammatory Response

NF-κB is a transcription factor that enters the nucleus and acts as an inflammatory
mediator by upregulating various pro-inflammatory genes. The dysregulation of this gene
leads to the runaway inflammation found in several pathological conditions (Figure 5).
NF-κB is modulated in one of two ways: the canonical and non-canonical pathway. The
canonical pathway is handled by the IKK complex composed of IKKα and IKKβ, and
NF-κB essential modulator (NEMO) or IKKγ [48]. The IKK complex can be stimulated by
extracellular stimuli, but most predominantly by TNF-α and IL-1 [42]. After activation,
IKK phosphorylates the molecule IκB, an inhibitor bound to NF-κB, and releases NF-κB
to regulate gene expression within the nucleus [46,48] (Figure 5). The non-canonical or
alternative pathway begins with the activation of NF-κB-inducing kinase (NIK). NIK then
phosphorylates IKKα, which stimulates the processing of the p100 protein into p52, the
active subunit that then binds RelB. Following activation, RelB enters the nucleus and
upregulates its target genes [49,50].
The non-canonical pathway is the pathway that is highly associated with obesity and
diabetes. A 2009 study designed to increase the obesity of obese mice on a high-fat diet
identified another subunit of IKK called IKKε. Mice with the IKKε gene removed that were
fed a high-fat diet that induced obesity showed an upregulation of UPC1 in BAT and had
Int. J. Mol. Sci. 2022, 23, 9267 10 of 25

normal insulin sensitivity [51]. The results of this study link IKKε directly to an induction
of obesity on a high-fat diet and indicate that the lack of IKKε has protective effects.
The IKKε gene is induced by a caloric surplus and transcriptionally by NF-κB. Type 2
diabetes also increases in the activation of NF-κB due to the chronic inflammation already
present in the other immune cells and adipokines, hyperglycemia, TLR4 activation by the
high circulation of free fatty acids, and stress/damage to the endoplasmic reticulum [50]
(Figure 5). A possible explanation for the increased activation of the non-canonical NF-κB
is an increase in the activating ligands CD40L, LIGHT, and lymphotoxin found in diabetic
patients. Increased activation of the non-canonical pathway appears to be detrimental
to the insulin-producing β-cells [50]. One study examined another aspect of the non-
canonical pathway believed to contribute to the development of diabetes from the chronic
inflammatory state of obesity. The NIK was overexpressed in the hepatocytes of obese
mice, leading to hyperglycemia due to increased glucagon activity and an environment of
glucose intolerance [52].

3.2. CNS Control and the Impact of Inflammation

Research indicates that a high-fat diet is a risk factor for diabetes in many ways, which
has a far-reaching impact within the CNS, particularly the hypothalamic region of the
brain. The hypothalamus regulates metabolic homeostasis and determines energy intake
stimulation (e.g., hunger) through hormones like leptin and ghrelin [53]. Inflammation
within the CNS progresses rapidly and begins days after initiating a high-fat diet. This
inflammation first impacts the hypothalamic arcuate nucleus (HAN) and causes injurious
effects to metabolic homeostasis in the form of dysregulating leptin levels which ignites
insulin resistance. Benomar identified that an increase of TLR4 in obese mice caused dysreg-
ulation due to a rise in the available saturated fatty acids [53]. The TLR4 activation impacts
the proopiomelanocortin (POMC) neurons located in the HAN through microglial action.
The POMC has a role in the anorexigenic effect on the regulation of energy expenditure
and food intake via hormones such as leptin [54,55]. Leptin levels dictate the expression of
POMC, with increased levels of leptin leading to increased expression of POMC, decreased
appetite, and increased metabolic rate. Another key population of neurons within the HAN
is the orexigenic (AgRP) that upregulates appetite when stimulated, partially through the
actions of ghrelin. Ghrelin is one of the stimulators of hunger and AgRP neurons. The
AgRP neurons sense hunger, increase adipose tissue, and reduce metabolic rate [56,57].
The inflammatory actions of microglia activated by TLR4 impact these AgRP neurons. Mi-
croglia action in the AgRP neuronal population has an inhibitory effect, which suppresses
the effect. This contradictory effect serves as a short-term protective mechanism against
the inflammation in the HAN caused by a high-fat diet. However, chronic inflammation
appears to cause microglia to contribute to the damage [55,58].

3.3. Role of Inflammation in Diabetes and Dementia

Alzheimer’s disease (AD), the result of “type 3” or “brain” diabetes, displays a charac-
teristic cognitive decline due to the amyloid fibril plaques and neuronal necrosis [13–16,59]
(Figure 3). Obesity and diabetes are significant risk factors for developing the disease
because a key mediator of the disease progression is insulin resistance within the brain
that contributes to the creation of the neurofibril tangles and necrosis. A misfolded ver-
sion of the brain-specific protein, tau, creates these tangles. Tau regulates insulin and
insulin growth factor-1 (IGF1); resistance to these two in the brain causes the upregulation
of glycogen synthase kinase 3β (GSK-3β). The increased activity of the kinase GSK-3β
hyper-phosphorylates tau and leads to misfolding and neurofibril aggregates [60]. The
hippocampus, associated with memory, is one of the areas with the highest concentrations
of the insulin receptor (IR), which links diabetes to AD [16]. Oxidative stress, an imbalance
between the reactive oxygen species and the system’s ability to negate these free radicals,
can propagate the progression of disease in diabetes and AD. Increased oxidative stress
leads to apoptosis due to mitochondrial dysfunction, peroxisomes, and damage to the
Int. J. Mol. Sci. 2022, 23, 9267 11 of 25

cellular membrane. This cell death contributes to the cognitive decline seen in patients
with AD [16,61].

4. Current Status of Research on Obesity, Diabetes, and Dementia

Research in the areas of obesity, diabetes, and dementia is ongoing and continues to
progress. Although the understanding of these conditions has grown rapidly in recent
years, much is still unknown, which leaves researchers with a dual goal of increasing the
knowledge of each disease as well as devising new treatments. Medications targeting the
POMC-MCR pathway, the traditional diabetes drug metformin, and the molecule Pdia4 are
all current research interests.

4.1. Studies on the POMC-MCR Pathway

The POMC neurons and associated leptin–melanocortin pathway is currently a main-
stay of obesity-based genetic research. Scientists believe the effect of the POMC gene offers
protection against the development of T2DM [62,63]. The POMC gene is a precursor for
three melanocortin peptides known as melanocyte-stimulating hormones (MSH)—α-MSH,
β-MSH, and γ2-MSH—and the molecule β-endorphin. These peptides and the molecule in-
teract with melanocortin receptors (MCRs) to decrease appetite and increase the metabolic
rate [62]. Recent rat model studies indicate that rats deficient in the POMC gene develop
obesity, glucose intolerance, and insulin resistance [58]. Older rat model studies clearly
identify α-MSH to be a potent appetite suppressor and stimulator of TRH through the
activation of MC4R [63]. In 2006, Tung et al. injected POMC-null mice with either α-MSH,
β-MSH, or γ2-MSH and allowed the mice to free feed. Mice treated with α-MSH showed
the largest decrease in body mass and food intake after a single dose compared to mice
treated with β-MSH and γ2-MSH [62,64]. Because rodents do not express β-MSH due to a
lack of an N-terminal proteolytic site that allows cleavage and production of the protein,
the β-MSH effects were unclear.
More recent studies elucidated the role of β-MSH via the Labrador retriever animal
model [60]. Compared to the rat model (69%), the canine model (79%) offered a greater
degree of genetic similarity in the POMC gene because Labrador retrievers have the highest
prevalence of obesity among dog breeds and have similar comorbidities as humans. In
2016, Raffan et al. studied a cohort of 310 Labrador retrievers classified as assistance dogs
to determine the effect of the naturally occurring 14-bp deletion of the POMC gene. This
deletion prevents the production of β- on POMC-MCR MSH and β-endorphin, both of
which are associated with hyperphagia, increased adiposity, and loss of appetite control.
Labradors with the mutation showed higher body weight and increased food intake
motivation behaviors [65].

Drugs Utilizing the POMC-MCR Pathway for Obesity Treatment

Scientists are investigating new obesity drugs based on the POMC-MCR pathway
studies to further illuminate the genetic mechanisms partially responsible for the devel-
opment of obesity [66]. MC4R agonists, designed to stimulate the MC4R in place of the
POMC ligands, are a well-researched therapeutic route that reduces adiposity and appetite;
however, most of these agonists have cardiovascular drawbacks, such as hypertension.
Two MC4R agonists under research are LY2112688 and a new FDA-approved drug called
Setmelanotide (BIM-22493).
In a double-blind pharmaceutical trial, researchers administered the MC4R agonist
LY2112688 to a mix of obese men and women who were either MC4R deficient or MC4R
sufficient (control group). Administration of LY2112688 yielded a higher incidence of
hypertension in the MC4R-deficient group than the control group [66]. However, not
all MC4R agonists have a hypertensive effect [67]. The new drug, Setmelanotide, is an
eight-amino acid cyclic peptide labeled as BIM-22493 or RM-493 that functions as an MC4R
agonist to treat the monogenic causes of obesity caused by POMC deficiency by lowering
food intake and restoring insulin sensitivity [67,68].
Int. J. Mol. Sci. 2022, 23, 9267 12 of 25

A phase II, non-randomized, open-label human study conducted in 2016 by Kühnen et al.
examined the effects of Setmelanotide in two obese POMC-deficient patients. Patient 1
was a 21-year-old female with a heterozygous loss-of-function mutation in the POMC gene
and early-onset childhood obesity. Patient 2 was a 26-year-old female with a homozygous
loss-of-function mutation in the POMC gene. Both patients reported a 9/10 score on the
Likert hunger scale (0 = no hunger, 10 = extreme hunger), indicating a high degree of
hyperphagia. Both patients were injected subcutaneously once daily with Setmelanotide.
Patient 1 received 0.25 mg and Patient 2 received 0.5 mg, with both patients receiving
incremental dose increases of 0.5 mg per week. Both patients reported a decreased appetite
with increased dosages, with their Likert hunger scores reported as a 0 or 1 at a dose of
1.5 mg. Both patients exhibited significant weight reduction while on the drug. However,
the cessation of Setmelanotide resulted in an increase in Patient 1’s hunger levels to a 7 on
the Likert hunger score and a weight gain of 4.8 kg. Minimal side effects (e.g., dry mouth,
pain at injection site) were reported and did not include any hypertensive effects [67,68].
Tests of Setmelanotide on Rhesus macaques resulted in a 35% transient decrease in
intake and a 13.5% body mass weight loss in the 8-week treatment course. The results
indicated that 0.5 mg/kg/day dosing of BIM-22493 in male Rhesus macaques reduced food
intake. However, this effect was only temporary after the treatment stopped. A comparison
of LY2112688 and BIM-22493 in primates revealed that a comparable dose of BIM-22493
had a higher decrease in food intake than LY2112688 [69]. Notably, BIM-22493 did not alter
either blood pressure or heart rate. Similar studies conducted with mice, rats, and dogs
yielded comparable weight loss results [69,70].

4.2. Effect of Metformin in the Treatment and Prevention of Dementia

Studies on metformin, the drug of choice for T2DM, show promising improvements
in cognition as well as disease progression [71]. Metformin, derived from the plant
Galega officinalis (specifically the product galegine), has a mechanism of action that is not
fully understood. Researchers believe metformin either inhibits mitochondrial respiration,
mitochondrial glycerophosphate dehydrogenase, or alters lysosome activity likely using
an AMP-activated protein kinase (AMPK)-dependent mechanism [72,73]. Due to the close
link between T2DM and AD, a double-blind, randomized, placebo-controlled crossover
pilot study examined the effects of metformin on the CNS in non-diabetic AD patients
with mild cognitive impairments. The data collected indicated that metformin penetrates
the blood–brain barrier (BBB) as measured in the CSF. Metformin-treated patients showed
improved cognition related to memory, learning ability, and attention/focus abilities. The
placebo group did not yield these same results [74].
A more recent 2021 study investigated the cognitive and physiological effects of
metformin in late middle-aged mice [73]. The 10-week trial used 59 male C57BL6/J mice.
The treatment group received oral 100 mg/kg/day doses of metformin. Mice treated
with metformin displayed improved memory and functioning, general and neural anti-
inflammatory effects, and increased AMPK activation [73]. The improved memory seems to
be linked to the increase of autophagy within the hippocampus, as lower rates of autophagy
are associated with aging and impaired cognitive function. Neuro-inflammation is another
hallmark of aging, particularly within the hippocampus [75,76]. This inflammation is
mediated by the immune cells within the brain, microglia, and astrocytes that release
pro-inflammatory cytokines. The examination of neural tissue post-metformin treatment
revealed microglia activated to the anti-inflammatory M2 phenotype and reduced amounts
of microglia present, which led to a lower measured concentration of the cytokines TNF-α
and IL-1β [75]. Another pertinent anti-inflammatory effect was metformin’s inhibition of
NF-κB in the treated mice [73].

4.3. Studies Utilizing Pdia4 to Treat Diabetes

Recent research offers novel insight into the understanding of the pathogenesis of
diabetes and could yield a new treatment. A 2021 study utilized a mouse model to explore
Int. J. Mol. Sci. 2022, 23, 9267 13 of 25

the role of protein disulfide isomerase family A, member 4 (Pdia4), in the regulation
and dysfunction of β-cells and the role it plays in the development of diabetes. Pdai4 is
a member of the protein disulfide isomerase (PDI) family [77]. This family of proteins
serves as oxidoreductases and chaperones that catalyze disulfide bonds, maintaining other
proteins conformations, and regulating other protein interactions. Malfunctions in PDIs
lead to various diseases, such as diabetes, obesity, dementia, cancer, and cardiovascular
pathologies [78].
The Kuo et al. (2021) study revealed that Pdia4 was paramount in ROS produc-
tion, leading to pancreatic β-cell failure and the development of diabetes [77]. The study
also showed that the use of Pdia40 s inhibitor, 2-β-D-glucopyranosyloxy1-hydroxytrideca
5,7,9,11-tetrayne (GHTT), prevented the activation of the pathway responsible for ROS
production and improved diabetic symptoms via improvements in β-cell function. Sci-
entists made these conclusions using a detailed mouse model utilizing Lepr db/db mice,
which model phase 1 to 3 of T2DM and obesity. The Lepr db/db mice had an increased
expression of Pdia4 in their pancreatic β-cells. Following this discovery, the researchers
bred mice with the Pdia4 gene knocked out, with Lepr db/db mice and their offspring,
which were Pdia 4-/-Lepr db/db, exhibiting borderline diabetes with a later onset than
Lepr db/db offspring with the Pdia4 gene present. The researchers gave the Pdia4 inhibitor,
GHTT, orally to Lepr db/db mice in 1-, 5-, and 25-mg/kg doses from 8 to 24 weeks of age.
GHTT reduced the pancreatic β-cell atrophy and ROS production induced by Pdia4 [77].
The role of Pdia4 and its inhibition in the pathogenesis and potential slowing of diabetic
progression is promising and warrants further research.

5. Diets That Affect Obesity

Obesity is derived through a combination of genetic and environmental factors. Al-
though genetics can predispose individuals to obesity, the evolution of nutrition (particu-
larly the Western diet) is a major contributor to the issue (Figure 6). As discussed, obesity is
an inflammatory condition. Certain diets are pro-inflammatory, which promote the develop-
ment of obesity, diabetes, and thus dementia [79,80]. These pro-inflammatory diets cause an
increase in reactive oxygen species (ROS), insulin resistance (IR), and dysregulation in the
activation of the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone
system (RAAS) that contributes to the increase in obesity and related conditions [81]. The
Western diet (WD) is the most prominent of these pro-inflammatory diets; however, diets
such as the Mediterranean diet (MD) lower inflammation and decrease health risks.

5.1. Western Diet (WD)

The ideal diet to maintain a healthy weight as recommended by the CDC’s “Dietary
Guidelines for Americans 2020–2025” includes the following: 2.5 cups of vegetables, 2 cups
of fruit, 6 ounces of grains, 3 cups of dairy, and 5.5 ounces of protein a day (avoiding red
meat) [82]. These guidelines also stipulate that caloric intake should be 240 kcal or lower a
day, with less than 10% of the caloric intake from either added sugars or saturated fats [82].
Furthermore, the American Heart Association recommends less than 6 teaspoons of sugar per
day for men and less than 9 teaspoons for women [83]. It is also important to note that these
guidelines can be adjusted for age, gender, level of physical activity, and other altering factors.
Although these guidelines offer a balanced way of eating, this is not the prominent diet
within the US or the Western world. Instead, the dominant WD correlates with the rise in obe-
sity [82]. The WD is the antithesis of the recommended dietary guidelines. The bulk of the
caloric intake in the WD comes from food rich in sugar, saturated and trans fats, carbohydrates,
salt, and red meat [82]. The WD also deemphasizes vegetables and fruits. One of the major
contributors to the pro-inflammatory environment is the imbalance of omega-6 to omega-3
ratio. A high ratio, caused by a dramatic increase in omega-6 levels, is pro-inflammatory
(Figure 6). The emphasis on saturated and trans fats and vegetable oils in the WD diet
creates an average ratio of 20:1 [81].
Int. J. Mol. Sci. 2022, 23, 9267 14 of 25

Figure 6. Comparison of the Western diet versus the Mediterranean diet. The Western diet and
its associated fatty foods are heavily linked to the causation of obesity and insulin resistance due
to the induction of oxidative stress through the creation of reactive oxidative species and the pro-
inflammatory environment that it creates. In contrast, the Mediterranean diet is low in fat, sugar, and
red meat, and offers plant-based options. This leads to a greater concentration of antioxidants, which
combat ROS and soothe inflammation.

Research indicates the continued implementation of the WD, which is based on de-
sirable, high-calorie foods and causes addictive behaviors such as binge or stress eating
through disturbances in hypothalamic–pituitary–adrenal axis regulation [84,85]. This
disturbance starts the cycle that creates obesity and related cognitive problems. The hip-
pocampus handles memory, but it also plays a role in decision making and the WD-induced
disturbances lower the ability of the hippocampus to regulate food intake, leading to
overeating [84,86]. This hippocampal disturbance and the addictive behaviors stimulated
by the high-fat, sugary foods are a powerful combination that perpetuates obesity [84].
Oxidative stress and insulin resistance are two major problems prompted by the
WD [87,88]. The high-sugar, calorically dense foods prompt more insulin release, but
the timing of food intake is also important. Often the WD includes constant snacking,
leaving the body in the postprandial state, with constantly elevated insulin levels. This
hyperinsulinemia is a likely cause of IR, and thus contributes to the development of T2DM
and obesity [88,89]. The constant postprandial phase also contributes to the creation and
imbalance of ROS free radicals, which creates a pro-inflammatory environment and also
helps derive IR. The nutrient excess of the WD increases ROS [87]. Excessive nutrients
translate into an increased electron supply, which, without an increase in demand for
energy molecules (ATP), leads to a raised mitochondrial membrane potential. This increase
in membrane potential causes the increase in ROS during oxidative phosphorylation [81].
Int. J. Mol. Sci. 2022, 23, 9267 15 of 25

This mechanism is a contributor to the NF-κB-mediated inflammation and IL-6 release from
adipocytes [90].
The activation of the SNS and RAAS are also contributors to IR and the inflammatory
state. The SNS serves as a regulating system using the catecholamines epinephrine and
norepinephrine to control several physiological aspects, such as the resting metabolic rate
and catabolic metabolism, thermogenesis, food intake, and blood pressure [91,92]. Obese
individuals have increased SNS activity, which translates into hypertension and increased
insulin resistance [93]. Insulin serves as an activator of the SNS and hyperinsulinemia
causes a radical increase in SNS activity that leads to catabolism, hypertension, and an
increase in RAAS activity. The RAAS system is a hormonal regulatory system based in
the kidneys and helps to maintain blood pressure. These system effects are mediated by
the peptide angiotensin II (ANG II), which is the product made from the breakdown of
angiotensinogen. The RAAS system may have a basis in the kidneys, but it is important
to note that adipocytes can make up to 30% of the body’s angiotensinogen and begin the
RAAS cascade [94]. The overactivation of the RAAS system perpetuates hypertension and
IR through the induction of oxidative stress, which cycles back around to the inflammatory
state associated with obesity, T2DM, and AD [81].

5.2. Mediterranean Diet (MD)

In contrast to the WD, the MD is anti-inflammatory and has several health benefits,
with research indicating that it is the best diet to combat obesity [95,96]. The MD is
defined by the consumption of a majority of plant-based foods (e.g., vegetables, fruits,
nuts, seeds, olive oil), low to moderate amounts of dairy and lean meat (e.g., poultry, fish),
and minimal amounts of red meat and eggs [96]. The MD has a positive correlation with
antioxidants (e.g., glutathione peroxidase, superoxide dismutase) that offer protection
against the generation of ROS [97] (Figure 6). The health benefits, if followed during
pregnancy, include the decreased risk of neural tube defects in the fetus and a reduced
tendency for the offspring to become obese, likely through epigenetic mechanisms [96].
Studies indicate that the MD is effective in inducing weight loss, particularly when dieters
switch from the WD to the MD. However, a 2020 study found that participants who
followed the MD were twice as likely to maintain their weight loss [98].

6. Current Therapeutics
Obesity, diabetes, and dementia are all interrelated, so there is no surprise that their
treatments are also interconnected in various ways [99]. Obesity is an imbalance of energy
input and energy expenditure at the most fundamental level. The current baseline treatment
plan, assuming no other underlying conditions exist, is to correct this imbalance with
a caloric deficit. A caloric deficit can be created by a combination of lowering caloric
intake and increasing physical activity. Although a caloric deficit is paramount, nutrition
alterations are also recommended [96]. Healthier food choices, such as switching from the
WD to the MD, or a more plant-based diet, offer more benefits that simply losing weight
(Figure 6). A healthier diet lowers the risk of developing cardiovascular conditions and
dementia [96]. Current guidelines recommend losing 5–10% of body weight within the first
6 months [100]. The combination of calorie restriction and incorporating antioxidant-rich
foods helps decrease the inflammatory state and causative oxidative stress [100].

6.1. Diet and Lifestyle Modifications

The implementation of lifestyle modifications is paramount to prevent disease. Obesity
causes chronic health conditions that can drastically shorten and lower the quality of
life [1,2]. All of these chronic conditions could be managed or prevented by following a
more plant-based diet and introducing regular exercise, especially if implemented at a
young age [1]. The current increase in the use of the WD has led to a rise in obesity, especially
in children and expectant mothers. Within the United States, the obesity prevalence among
children aged 2–19 years was 19.7% during the years of 2017–2020 and this percentage has
Int. J. Mol. Sci. 2022, 23, 9267 16 of 25

continued to steadily increase [101]. Obesity at a young age is extremely detrimental as

children usually become obese adults with early development of diabetes and all of its
complications, including dementia [102]. The prevention of obesity using proper nutrition
management and physical exercise should begin at a young age to prevent complications.
These small changes in childhood can manifest good results: (1) avoid overfeeding infants
(bottle feeding is associated with a greater risk of excessive caloric intake), (2) reduce
sedentary and electronic use time, (3) aim for 1 h of physical activity per day for children
3–5 years of age, and (4) limit children’s fat intake to less than 30% of caloric intake [103]. In
adulthood, obesity lifestyle modifications remain the gold standard for treatment. Calorie
restriction is the foundation for the treatment and prevention of obesity, diabetes, and
dementia [104].
Additional dietary interventions (e.g., certain vitamins and nutrients frequently found
in plant-based foods) in tandem with calorie restriction is especially promising at subverting
AD [102]. Dietary adjustments, such as incorporating foods rich in omega-3 polyunsatu-
rated fatty acids, curcumin, flavonoids (natural components found in plants), minerals (e.g.,
calcium, magnesium, potassium), and drinking caffeine are proven to lower the risk for AD
by increasing the antioxidants in the body and lowering the amount of inflammation within
the body and brain [102,105–109]. Although the incorporation of foods rich in anti-oxidants
is important and offers several anti-aging health benefits, cutting out high-fat, processed,
and sugary foods is also critical.
Another key lifestyle modification is the incorporation of or increase in physical
activity. Regular exercise offers several health advantages, including a reduction in body
weight, better glycemic control, a reduction in dyslipidemia, and a decrease in the amount
of Aβ aggregates that are associated with cognitive decline and AD [102,110,111]. Exercise
can take many forms, such as 30-min daily walks, weight training, or playing sports with
friends [112]. The utilization of consistent lifestyle changes offers society the chance to
prevent chronic conditions such as obesity, diabetes, and dementia, and also serves as the
primary method of treatment.

6.2. Pharmaceutical and Surgical Options for Obesity Treatment

There are also a variety of other treatment options to aid the weight loss process, such as
medications, weight loss devices, and bariatric surgery. These additional methods are meant to
be used in conjunction with a change in diet and increase in activity, and not to replace traditional
weight-loss methods. As of 2021, the Food and Drug Administration (FDA) has approved five
medications for this purpose: orlistat (Xenical, Alli), phentermine/topiramate (Qsymia), na-
ltrexone/bupropion (Contrave), liraglutide (Saxenda), and semaglutide (Wegovy) [113]. The
drugs have the following mechanism of actions: (1) Xenical and Alli remain active in the
gut and lower fat absorption, (2) Qsymia suppresses appetite by stimulating the sensation
of satiety, (3) Contrave aids in addiction cessation and lowers appetite, (4) Saxenda lowers
appetite by mimicking the hormone glucagon-like peptide-1 (GLP1), which acts in the
brain to regulate food intake, and (5) Wegovy, which also controls the appetite via GLP1.
These medications are currently approved for long-term use [113,114]. The FDA has also
approved four weight loss devices: (1) gastric bands placed around the upper portion of
the stomach, (2) electrical stimulation systems placed in the abdomen that block gastric
and CNS communication, (3) gastric balloon systems (an inflatable balloon placed into
the stomach and once inflated it both lowers the area available in the stomach and delays
gastric emptying); and (4) gastric emptying systems involving the insertion of a tube into
the stomach that drains food out of the abdomen [114] (Figure 7).
Weight-management devices are another method of regulating body weight, with two
currently FDA-approved: (1) an oral removable palatal space-occupying device that limits
food intake by forcing smaller bite sizes and slowing eating, and (2) ingested, transient
space-occupying devices that temporarily enter and fill the stomach [114]. In the cases of
severe obesity (BMI > 40 or BMI of 35–40 with comorbidities), bariatric surgery is a potential
therapeutic option. The bariatric surgical procedure decreases the stomach size and alters
Int. J. Mol. Sci. 2022, 23, 9267 17 of 25

how food moves through the gastrointestinal system. This type of surgery is generally
done by either the Roux-en-Y gastrojejunostomy or sleeve gastrectomy method. Although
this procedure does show excellent weight-loss results, it is not without risk [115,116].

Figure 7. Similarities of the therapeutics for obesity, diabetes mellitus, and dementia. Because
obesity, diabetes, and dementia are so closely related, several aspects of their treatments overlap.
Lifestyle modifications (e.g., change in diet, increase in exercise) are the most effective means of
treating or preventing all three conditions; however, several medications and surgical options are
available to aid in the management and treatment of these conditions.

6.3. Therapeutics for Diabetes Mellitus

The management of diabetes is dependent on whether it is classified as type 1 or
type 2, with weight loss recommended for both types if the patient is classified as over-
weight or obese. In accordance with the American Diabetic Association 2022 guidelines,
insulin administration is the primary treatment for type 1 diabetes [117]. The regimen is
currently stated as a basal amount of insulin with mealtime and correctional insulin. It is
recommended to use a long-acting insulin analog for basal insulin management because
it is associated with steadier plasma concentrations and fewer hypoglycemic effects [117].
Recently, the FDA approved two hybrid closed-loop pump systems with evidence that
this automated insulin injection system puts patients in their target glycemic range more
efficiently and for a longer period of time compared to the alternative senor-augmented
pump. Non-insulin-based treatments for type 1 diabetes include glucose-lowering drugs
(e.g., Pramlintide, GLP1 receptor antagonists, sodium–glucose cotransporter-2 (SGLT2)
inhibitors) and pancreas and islet transplantation [117].
T2DM is patient-dependent and managed through pharmacological methods and
lifestyle modifications. Metformin is an oral medication that is the first-line therapy
(Figure 7). It can be given as either a twice-daily immediate-release dose or as a once-
daily extended-release dose. For patients with a blood glucose of over 300 mg/dL, insulin
therapy can be initiated to quell the hyperglycemia, but it is preferable to use non-insulin
therapies whenever possible. T2DM is a chronic disease, and over time, metformin alone
may not offer sufficient glycemic control. In the event of the waning effectivity of monother-
apy, other medications (e.g., GLP1 receptor agonists, SLGT2 inhibitors) can be added as
needed on a patient-by-patient basis [117]. There is now evidence from the Vildagliptin
efficacy in combination with metformin for the early treatment of type 2 diabetes that an
early combination therapy of metformin and dipeptidyl peptidase could offer potential
Int. J. Mol. Sci. 2022, 23, 9267 18 of 25

benefits [118]. Lifestyle modifications fall in line with the recommendations and guidelines
surrounding obesity management, emphasizing healthier meals. The important distinction
between merely trying to lose weight and controlling diabetes through dietary management
is the removal of sugar-containing diets and lowering carbohydrate intake [119].

6.4. Therapeutics for Dementia

Dementia—like diabetes—is a chronic, progressive mental illness that cannot be cured;
however, it can be managed with the treatment goal of maintaining and improving the
quality of life. The treatment plan for dementia consists of a healthy lifestyle (regular exer-
cise and heathy diet), pharmacological intervention, and occupational therapy. Previously,
there were only two types of pharmacological treatment options available: cholinesterase
inhibitors (e.g., donepezil, rivastigmine, galantamine) that raise the levels of acetylcholine
and a N-methyl-D-aspartate receptor antagonist (memantine), and a glutamate regulator
(Figure 7). Both drugs work to protect the brain’s ability to maintain learning activity and
memories [120–122].
In 2021, a novel drug, Aducanumab, received FDA approval to treat AD. Aducanumab
is a human IgG1 anti-Aβ monoclonal antibody that selects for Aβ aggregates, which are
the basis of the disease’s amyloid plaques and neurofibrillary tangles. Aβ aggregates are
thought to begin building up to two decades before the onset of symptoms. The drug is
given intravenously once a month. Aducanumab is the first disease-modifying AD that
can remove and prevent the buildup of amyloid plaques. The treatment offers a potential
breakthrough in AD management and prevention; however, there is much current debate
surrounding the drug’s use and effectivity [121]. The controversy surrounding the novel
drug and associated accelerated FDA approval are founded on the uncertainty of the exact
mechanism of AD. Aducanumab targets the accumulation of Aβ aggregates that are in-
volved in the disease process, but it is unknown whether amyloid buildup is the exact cause
of impaired cognition for both early-onset and late-onset AD. Furthermore, human clinical
trials did not prove that the drug effectively improves memory or cognitive functioning.
Human clinical trials are still ongoing to continue to explore the drug and clinical benefit in
accordance with the accelerated approval track implemented by the FDA [123]. Although
pharmacological therapeutics often take center stage in AD, occupational therapy is another
step in general dementia management. Therapists can work with patients to help them
make the environment safer (e.g., remove fall risks, sharp items), manage the behavioral
changes associated with altered cognitive functioning, and help patients break down tasks
into more manageable steps [120].

7. Conclusions and Future Directions

Obesity, diabetes, and dementia are highly prevalent chronic diseases within the US
population, and the incidence of these diseases has increased over the past several decades.
The dominant explanation for this trend incorporates a wide spectrum of factors, such
as age, gender, genetics and epigenetics, socioeconomic status, inflammation, and diet.
A search of the current literature indicates a strong positive correlation between obesity
and the development of diabetes, particularly type 2. The chronic inflammatory damage
caused in the brain by type 2 diabetes is so closely associated with the development of
dementia that it has been labeled as “type 3” or “brain diabetes”. One of the predominant
causes for the rise in these conditions is the HFD, including the Western diet (WD), which
stimulates the inflammatory response mediated by NF-κB and its associated cytokines
and the oxidative stress and an increase in the production of reactive oxidative species.
Although lifestyle modifications (e.g., healthy diet, regular exercise) are the recommended
treatment for obesity and the prevention of diabetes and dementia, other treatment options
(e.g., surgery) and aids (e.g., pharmacological appetite suppressants and mechanical devices
to limit food intake) are now available for prevention.
This article discusses the role that obesity plays in the development of diabetes and
dementia and presents current research on new molecular biology treatments designed to
Int. J. Mol. Sci. 2022, 23, 9267 19 of 25

improve the treatment of obesity, diabetes, and dementia. These new treatments include: (1)
Setmelanotide—an MC4R agonist used to treat genetically-stimulated obesity and (2) Pdia4
inhibitor (GHTT)—a drug used to improve pancreatic β-cell function in diabetic patients.
As technology and understanding continue to develop, further research could clarify the
pathogenesis of disease and offer novel treatment options.

Author Contributions: A.S., A.P.R. and P.H.R. contributed to the conceptualization and formatting
of the article. A.S., S.B., A.P.R., J.C. and P.H.R. were responsible for writing, original draft preparation,
and finalization of the manuscript. A.P.R. and P.H.R. were responsible for the funding acquisition.
All authors agreed to publish the contents. All authors have read and agreed to the published version
of the manuscript.
Funding: The research presented in this article was supported by NIH grants AG042178, AG047812,
NS205473, AG060767, AG069333, and AG066347 (to P.H.R.), Alzheimer’s Association through a SAGA
grant, Garrison Family Foundation Grant, and NIH grants AG063162 and AG071560 (to A.P.R.).
Institutional Review Board Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

WD Western diet
MD Mediterranean diet
T2DM Type 2 diabetes mellitus
T3DM Type 3 diabetes mellitus
CDC Centers for Disease Control and Prevention
BMI Body mass index
AD Alzheimer’s disease
FTD Frontotemporal dementia
LBD Lewy body dementia
VD Vascular dementia
WAT White adipose tissue
TNF-α Tumor necrosis factor alpha
IL-6 Interleukin 6
SVF Stromal vascular fraction
SREBP Sterol regulatory element-binding protein
FTO Fat mass and obesity-related
LEPR Leptin receptor
MCR4 Melanocontin 4 receptor
SNP Single nucleotide polymorphism
PCOS Polycystic ovary syndrome
INSIG2 Insulin-induced gene 2
PCKS1 Proprotein convertase subtilisin/kexin type 1
PPARG Peroxisome proliferator-activated receptor gamma
BAT Brown adipose tissue
UPC1 Uncoupling protein 1
miRNA Micro-RNA
HFD High-fat diet
IGF Insulin growth factor
RXRα Retinoid X receptor alpha gene
CNS Central nervous system
HDAC Histone deacetylase
IGF2 Insulin-like growth factor 2
TLR4 Toll-like receptor 4
NEMO NF-κB essential modulator
GSK-3β Glycogen synthase kinase 3β
HAN Hypothalamic arcuate nucleus
KCNQ1 Potassium channel voltage gated KQT-like subfamily member 1 (KCNQ1)
Int. J. Mol. Sci. 2022, 23, 9267 20 of 25

KLF14 Kruppel-like factor 14

MSH Melanocyte-stimulating hormone
MCRs Melanocortin receptors
POMC Proopio melanocortin
DNA Deoxyribonucleic acid
ROS Reactive oxygen species
IR Insulin resistance
SNS Sympathetic nervous system
GHTT Glucopyranosyloxy1-hydroxytrideca
CRP C-reactive protein
PDI Protein disulfide isomerase
ER Endoplasmic reticulum
MDD Major depressive disorder
CFS Cerebrospinal fluid
FDA Federal Drug Administration
ARC Arcuate nucleus
MRI Magnetic resonance imaging
BBB Blood–brain barrier
PUFA Polyunsaturated fatty acids
AMPK AMP activated protein kinase
US United States

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