Journal of Diabetes Mellitus and Metabolic Syndrome

Journal of Diabetes Mellitus and Metabolic Syndrome Zygoscient Research

Insights 1

Diet Composition for the Management of Obesity and Obesity-related

*Rachel Botchlett1
, Chaodong Wu2
Pinnacle Clinical Research, Live Oak, TX, 78233, USA
Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77843, USA
Review Article
Citation: Rachel Botchlett (2018) “Diet Composition for the Management of Obesity and Obesity-related Disorders.” j. of diabetes mellit. and metab. syndr. vol. 3,
Received 14/06/2018
Accepted 14/09/2018
Published 19/09/2018
*For Correspondence
Rachel Botchlett
Pinnacle Clinical Research,
Live Oak, TX, 78233, USA
Fax: 210 572 5766
Keywords: Obesity, Type 2 Diabetes, Hypertension, NonAlcoholic
Fatty Liver Disease, Dietary Interventions, Diet
Running Title: Diet composition in obesity


Healthy nutrition is essential for the prevention of disease and for
maintenance or promotion of health; although healthy
nutrition remains to be precisely defined. Over the past
several decades, various types of nutrients have been
functionally validated and considered as critical components
of healthy nutrition, which commonly includes fiber-enriched
carbohydrates, mono- or poly-unsaturated fatty acids,
essential amino acids, and certain micronutrients. When
managing obesity and obesity-associated metabolic diseases,
much attention has been paid to the content of nutrients that
is considered as healthy nutrition. Accumulating evidence
also suggests that nutrient composition could be more
important than the content of individual nutrients in the
context of reducing body weight and obesity-associated risk
for metabolic diseases. Consistently, it would be more
important to focus on a diet with differences in nutrient ratios
rather than individual type(s) of nutrients in terms of
managing obesity and metabolic diseases. In this review,
recent advances in the dietary management of obesity and
obesity-related metabolic diseases have been discussed. This
the review also has highlighted several specific diet compositions
and their differences in managing hypertension, type 2
diabetes, and non-alcoholic fatty liver disease.
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Prevalence rates of overweight and obesity have dramatically increased within the United States over the past
several decades. The most recent data from the CDC and nutritional health and examination surveys (NHANES)
estimate that 70% of American adults are overweight or obese [1]. The prevalence rate of obesity specifically, from
2011-2014, was roughly 36.5% of adults aged 20 and older [1]. Given the significant association between obesity
and chronic metabolic disorders, the increased prevalence of concomitant comorbidities is no surprise. In fact, the
rate of type 2 diabetes mellitus (T2DM) within North America and the Caribbean has increased from 7.6% to
approximately 10% from 2003-2013 [2]. Rates of hypertension and chronic liver diseases, such as non-alcoholic
fatty liver disease (NAFLD), have also increased over recent years[3]
Given the epidemic nature of obesity, much research has focused on lifestyle and pharmaceutical interventions [4,
5]. Weight loss remains the most effective approach for obesity and reducing the risk of related diseases; however,
weight loss can be difficult to achieve and maintain [6, 7]. Multiple pharmaceuticals have thus attempted to reverse
obesity and offer “fast weight loss”; however, virtually all have been unsuccessful for various reasons. More
effective are the pharmaceuticals to manage obesity-related diseases. For example, angiotensin-converting
enzyme (ACE) inhibitors are useful for managing hypertension, while biguanides, thiazolidinediones, and
sulfonylureas are successful treatments for managing insulin signaling and systemic glucose utilization and thus,
hyperglycemia/T2DM [8-10]; Blood Pressure Lowering Treatment Trialists’ Collaboration, 2015 #3368. The
interventions for T2DM can subsequently aid in the management of NAFLD given their actions on stimulating
adipogenesis and uptake of free fatty acids, thereby reducing fat accumulation in the liver. Although great progress
has been made in the pharmaceutical industry, many of these interventions may be undesirable due to cost or risk
of side effects. Therefore, continued education on the benefits of diet as a lifestyle intervention is important now
more than ever. Several diets have proven very successful in maintaining obesity and obesity-related diseases [11]
The purpose of this review is to highlight such diets, particularly the specific diet compositions proven to be
effective in managing hypertension, T2DM, and NAFLD including details on the underlying mechanism(s).


The biggest factor leading to excess weight gain and the development of obesity is overnutrition. Energy
consumption that exceeds metabolic requirements leads to lipogenesis and fat storage within white adipose tissue
(WAT), the primary storage site of fat within the body. Overconsumption of dietary fat can lead to weight gain
relatively quickly since dietary fat is metabolized to free fatty acids, the primary substrate for triglycerides (TG) and
subsequently, lipid synthesis. However, overconsumption of any macronutrient can ultimately lead to fat synthesis
and accumulation. Therefore, the key dietary habit of reducing obesity is twofold: manage total caloric intake and
fat content within the diet.
Total Caloric Intake
The estimated daily caloric need for the average American male and female is approximately 2500 and 2000
calories, respectively (2015 – 2020 Dietary Guidelines for Americans, 8th Edition, December 2015; This estimate pertains to moderately active adults and has
remained relatively stable over the past several decades despite arguments as to the appropriate dietary
composition. Interestingly, much research has demonstrated that caloric restriction (CR) is highly beneficial in
managing obesity and stimulating weight loss. The majority of research focuses on three methods of CR: alternate
day fasting (ADF), which consists of a fasting day (0% – 25% of caloric need) alternating with a fed day (ad libitum
consumption), daily acute restriction (DAR) of ~ 25% of total calories, and intermittent fasting (IF). All three are
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shown to successfully induce weight loss in multiple obese populations [12, 13]; however, no one intervention seems
to be more beneficial than another [14]. Further, compliance rates are similar between the three approaches. It
seems that the success of each method is attributable to the slower rate of weight loss which stimulates lipolysis
while preserving lean body mass. Perhaps, ADF, DAR or IF may be more easily incorporated and maintained by
obese populations vs other methods of weight loss (“no-carb” diets, increased physical activity, etc). In addition to
weight loss, all three methods improve HBA1c, insulin levels, HOMA-IR score and several aspects of lipid
metabolism [15], all of which can be significantly impaired in obesity.
The overall mechanism tying CR to weight loss is obvious: fewer calories in equates to fewer calories stored. However,
the underlying mechanisms of CR and an improved metabolic profile are less understood. The majority of studies
conclude that CR, even periodically, leads to reduced inflammatory responses and production of oxidative stress.
For example, diet-induced obese rats subjected to CR of 40 % of ad libitum showed reduced hepatic triglycerides,
hepatic levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) and thus, levels of lipid
peroxidation and reduced impairment of fasting glucose [16]. Additional studies have demonstrated similar results
in other obese rodent models [17, 18]. Mechanistic studies in humans are limited, but few have demonstrated these
same findings in obese individuals [19-21]. It seems these mechanisms of CR also contribute to increased life span,
although this aspect is outside the scope of this review.

Fat Content

Dietary fat can have a significant impact on overall health and metabolism. Inadequate fat intake impairs
absorption of fat-soluble vitamins and leads to reduced production of hormones and lipoprotein particles, whereas
excess fat can contribute to inflammation, obesity, and steatosis in distal organs, for example, the liver. There is no
specific recommended daily intake (RDI) for total fat, but the current acceptable macronutrient distribution range
(AMDR) is 20-35% of total daily calories. Diets that exceed this range are labeled as high-fat diets (HFD) and
contribute to weight gain and a worsened metabolic profile. In rodents, this equates to weight gain relatively
quickly and increased inflammation and oxidative damage throughout the body [22-24]. HFD can result in similar
effects in humans, especially following chronic HFD, including weight gain/obesity, systemic inflammation, and
impaired glucose homeostasis. The primary mechanism underlying the metabolic effects of HFD is adipocyte
hypertrophy, which in turn contributes to increased expression of proinflammatory cytokines, impaired lipid
metabolism and ultimately, increased free fatty acids in the circulation which have damaging effects to many
tissues and cell types [5]. To prevent excess weight gain and/or promote weight loss and thus, limit this mechanism,
obese individuals are recommended to ingest a lower amount of total fat, all the while staying within the AMDR to
prevent metabolic problems caused by malnutrition.
Arguably more important than total fat for the management of obesity is monitoring the type of fat ingested.
Certain types of fat are known to be more detrimental than others and thus, can further exacerbate obesity-related
metabolic impairments. Saturated fat, in particular, is significantly more inflammatory compared to
unsaturated fat [25, 26] primarily through its potent ability to activate multiple inflammatory mechanisms including
macrophage infiltration and/or proinflammatory activation, and the c-Jun-N terminal kinase and TLR4 signaling
pathways [22, 23, 27, 28]. Saturated fat is also known to directly interfere with the insulin signaling cascade at multiple
steps [22, 23, 29, 30]. For these reasons numerous agencies, including the American Heart Association, American
Diabetes Association and USDA, recommend low saturated fat intake.
Micronutrients play an active role in virtually all aspects of metabolism including glucose homeostasis, fat
deposition, and protein metabolism. Thus, adequate intake is paramount in maintaining health and an appropriate
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body weight, and staving off metabolic disorders. Obesity is associated with several micronutrient deficiencies
including vitamins A, C and D, selenium, and thiamine [31-33]. In turn, these deficiencies can exacerbate the obese
phenotype and significantly contribute to the development of comorbidities, namely T2DM [31, 32]. For example,
an insufficient status of vitamin A and C are associated with leptin concentrations, and increased adipogenesis and fat
deposition [32, 34], while the deficiency in vitamin D is linked to reduced pancreatic ?-cell function [35]. Therefore, the
most important dietary approach related to micronutrients for the maintenance of obesity, and any subsequent
comorbidities, is adequate intake. This can be attained either through consumption of a wide variety of foods or
supplementation. It is important to note that the exact relationship between obesity and micronutrient
deficiencies remains unclear. Thus, additional research is needed to further explore the direction of causality.


The relationship between obesity and insulin resistance is well established. Excess weight gain and maximum lipid
storage ability of adipose tissue lead to abnormally enlarged adipocytes and subsequently, impaired lipid
metabolism and secretion of inflammatory cytokines within adipose tissue. Chronic overnutrition and/or obesity
and thus, inflammation within the adipose contribute to low-grade systemic inflammation, a major defining
characteristic of obesity. In fact, the term “metainflammation” is commonly used to describe the idea that
inflammation is the primary causal factor in many obesity-associated metabolic diseases, including insulin
resistance [36]. Indeed, several inflammatory cytokines are known to impair the insulin signaling cascade at multiple
sites in numerous tissues [37, 38]. Therefore, diet composition for managing obesity-related insulin resistance is
primarily aimed at preventing additional weight gain, with diets low in fat and simple carbohydrates but high in
fiber, and reducing the generation of inflammation and promoting insulin signaling via adequate intake of
Carbohydrates and Fiber
Overconsumption of carbohydrates, as with any macronutrient, can contribute to overnutrition and thus,
exacerbate the obese phenotype. However, monitoring the type of carbohydrate consumed seems more vital in
managing obesity-related insulin resistance. In both obese and non-obese patients, complex carbohydrates (such
as amylose and fibers) are associated with a reduced-risk for T2DM and insulin resistance compared with
consumption of primarily simple carbohydrates [39-41]. Animal studies using rodent models of diet-induced obesity
demonstrate similar results [42-44] and attribute the insulin desensitizing effects of simple carbohydrates to elevated
spikes in plasma glucose, stimulation of lipogenesis, and the promotion of proinflammatory mechanisms [45-47]
. For
this reason the current Dietary Guidelines for Americans (DGA) suggests limiting simple/refined grains such as
ready-to-eat cereals and white bread, and increasing intake of whole grains such as whole-wheat bread and
oatmeal (USDHHS). The underlying mechanisms and full effect(s) of simple versus complex carbohydrates on
human metabolism, especially in the context of obesity, remain relatively controversial; however, several clinical
trials are underway to further elucidate their role in insulin resistance and obesity [48]
Dietary fiber, which the DGA recommends 25g and 38g per day for women and men, respectively, promotes
colonic health regulates satiety and cholesterol levels, and slows the release of chyme into the small intestine,
which culminates in slower nutrient absorption (including glucose) through intestinal epithelial cells and ultimately,
reduced postprandial glucose responses. Indeed, multiple clinical trials and/or intervention studies in humans have
demonstrated that increased dietary fiber reduces fasting plasma glucose and HOMA-IR scores and is associated
with weight loss in obese and non-obese diabetic individuals [49-52]. Mechanistic studies in animal models
demonstrate that dietary fiber exerts these effects by improving lipid metabolism, reducing adiposity, and
increasing lean body mass [53, 54]
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Fat Content

A low-fat diet can greatly aid in the management of T2DM since it can help prevent weight gain and/or promote
weight loss. However, specific types of fats are more detrimental than others for managing insulin sensitivity. For
instance, because of their proinflammatory abilities, saturated fats are associated with impaired insulin signaling
throughout the body [22, 23, 55]. Multiple studies in both obese and non-obese diabetic adults have confirmed these
effects. For this reason, the DGA suggests the higher intake of unsaturated compared with saturated fats. Specifically,
adults should consume less than 10% of daily calories from saturated fat, and ingest a variety of unsaturated fats,
including mono- and polyunsaturated fats. Indeed, intervention studies have confirmed the benefits of following
such a diet. For example, a recent meta-analysis by Qian et al. concluded that diets higher in monounsaturated
fatty acids improve metabolic risk factors, including fasting glucose and HOMA-IR in patients with T2DM [56]
Replacing carbohydrates with either mono- or polyunsaturated fats can also greatly improve these factors [57]
Similarly, replacing saturated with polyunsaturated fats not only improves these factors but also reduces C-peptide,
which is known to have a significant negative correlation with insulin sensitivity [57]. It seems polyunsaturated fats
can also indirectly improve insulin sensitivity through its anti-inflammatory properties. For example, increased
intake of omega-3 polyunsaturated fatty acids lead to increased production of 3-series prostaglandins, which are
generally less inflammatory and more beneficial in several disease states than the otherwise produced 2-series [58]
For this reason a Mediterranean-style diet, which recommends a variety of healthy oils (i.e. mono- and
polyunsaturated fats), has been shown beneficial for maintaining T2DM [59]


Several micronutrients are shown to promote insulin signaling in humans, even in the presence of obesity,
including vitamins D and E, thiamine, and several minerals. Specifically, supplementation with vitamins D and E
contributes to enhanced systemic insulin sensitivity, as evidenced by improved HOMA-IR scores [60, 61], while the intake
of thiamine and zinc regulate fasting blood glucose and/or post-prandial glucose levels [62, 63] in patients with T2DM.
The latter dietary components and their subsequent effects are also likely to benefit patients with impaired fasting
glucose as they may slow the progression of hyperglycemia to diabetes. In overweight, diabetic individuals supplementation
with vitamin D, K and calcium similarly improves HOMA-IR scores, but also significantly increases
high-density lipoprotein (HDL) cholesterol and reduces fasting plasma glucose, insulin levels, and C-reactive protein
[64], an inflammatory marker linked to an increased risk for diabetes. Interestingly, it seems that vitamin D
supplementation is also beneficial in reducing the development of gestational diabetes [65], another condition
closely linked to obesity, although continued clinical research is necessary to further confirm its full effects.

Meal Timing

Meal timing can also be a key tool in successfully managing obesity-associated insulin resistance/T2DM. Much
research has previously established the relationship between circadian rhythm (i.e. sleep-wake cycles) and
metabolic elements in mammals, including genes that regulate glycolysis and insulin signaling [66-68]. More recently,
the association between disrupted sleep cycles and obesity and obesity-related diseases, including T2DM, has
been defined [69, 70]. Research to date has primarily revealed the cellular mechanisms but has yet to fully elucidate
how such mechanisms may be influenced by or interact within complex systems. Although clinical trials and/or
intervention studies specifically relating meal timing to circadian rhythm parameters are lacking, it is reasonable to
assume that syncing meals to specific points within the sleep-wake cycle would be beneficial to manage T2DM.
More research and clinical trials in this area are therefore warranted. Additionally, meal timing seems significant to
achieve successful weight loss [71], which is among the prescribed methods for preventing and managing T2DM.
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There are no current recommendations related to specific meal timing, but overall the DGA recommends multiple,
smaller meals throughout the day rather than a few, large meals.


Risk factors for cardiovascular disease (CVD) including hypertension and dyslipidemia are commonly found in
overweight and obese individuals. In fact, NHANES data from 2007-2010 showed prevalence rates of these
disorders at 35.7% and 49.7%, respectively in obese adults [72]. The link between obesity and CVD is a combination
of dietary factors, metabolic imbalances, and endothelial and vascular dysfunction [10]. Much research also points
to obesity-induced inflammation as a major contributing factor [10, 73]. Thus, interventions and dietary components,
including those discussed in previous sections, aimed to reduce obesity are of utmost importance. Indeed, weight
loss remains the key recommendation to manage all obesity-related conditions; however, additional dietary
components can greatly support heart health. These components collectively named the Dietary Approach for
Stopping Hypertension (DASH), and their underlying mechanism(s) are discussed in this section. Increased physical
activity is also a key intervention for managing excess weight gain and CVD; however, that topic is outside the
scope of this review.

Sodium Content

Sodium is an essential micronutrient that plays a critical role in maintaining blood volume and promoting nerve cell
transmission and muscle contraction. Because of the widespread use of sodium/table salt, sodium deficiencies are
infrequent in the average American adult. Excess intake, on the other hand, is exceptionally common, with average
daily consumption by Americans aged 2 and older at 3,400 mg. Overconsumption is linked to many metabolic
diseases with and without obesity [74-76]. The DGA, therefore, recommends a maximum intake of 2,300 mg sodium
per day, which is equivalent to about one teaspoon of table salt, although the DASH diet targets a maximum of
1,500 mg. Obese individuals who follow these dietary recommendations have shown reduced rates of
hypertension, atherosclerosis and lipid-induced oxidative stress and thus, a lowered risk of developing CVD [77]
Many studies show that even a moderate reduction in salt intake improves blood pressure both short and long-term.
Although perhaps less enjoyable, low-sodium diets seem to be a great dietary approach to manage obesity associated
disorders related to CVD as they are typically low risk and are generally easy to adhere. Another benefit
of reducing dietary sodium is that salt intake seems to be a potential risk factor for obesity itself, independent of
energy intake[78]

Carbohydrates, Fiber, and Cholesterol

The DASH diet recommends 55% of total daily intake from carbohydrates, including at least 3 servings of whole
grains per day. Indeed, evidence from clinical trials demonstrates that obese individuals who increase their intake
of whole grains show improvements in many factors associated with cardiovascular health [79, 80]. Additionally,
DASH targets 30 g of fiber per day for all individuals, which is in line with the DGA for average adults. Fiber is
specifically beneficial to heart health through its ability to reduce total and low-density lipoprotein (LDL)
cholesterol [81]. Interestingly, when compared with a low-carbohydrate diet, a diet high in fiber significantly
lowered atherogenic lipids, although both diets were effective for weight loss. It is well known that increased fiber
intake also reduces high blood pressure [82, 83]. Thus, these dietary components of the DASH diet help to manage
obesity-associated CVD through improvements in many known risk factors.
Although the DASH diet does not provide specific recommendations for cholesterol intake, it does target increased
consumption of fruits and vegetables and less caloric intake from non-lean meats. The mechanisms underlying the
success of these dietary approaches are the reductions in total and LDL cholesterol, increased HDL, and improved
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blood pressure [84, 85]. In fact, following the DASH diet seems to reduce most of the risks associated with the
metabolic syndrome which ultimately, contributes to improved cardiovascular health.


Unsurprisingly, the major micronutrients targeted by the DASH diet are the electrolytes. In addition to sodium
(discussed in detail above), potassium, magnesium, and vitamin D are important for proper management of heart
health. Obesity is associated with deficiencies of all three, which partially clarifies the mechanisms of obesity-associated
hypertension. For instance, in primary hypertension potassium depletion interrupts the normal functioning
of sodium pumps, increases sympathetic activity and angiotensin II production, and indirectly interferes with
calcium signaling [86]. Vitamin D deficiency, especially when paired with BMI ? 30, is also linked to arterial
hypertension and coronary artery disease, likely through inappropriate activation of the renin angiotensinaldosterone
system (RAAS) along with other mechanisms [87, 88]. Magnesium deficiency, commonly seen in in the
The United States, as evidenced by NHANES data from 2001-2010 [89], is shown to enhance angiotensin-induced
aldosterone synthesis and contribute to impaired insulin action [90, 91]. Thus, interventions to replete low
magnesium levels may be key to improving hypertension in diabetic individuals. Indeed, controlled interventions
using the DASH diet show repletion of all three macronutrients and subsequently, improvements in several risk
factors of CVD [92-94]. Interestingly, one trial demonstrated that the DASH diet lowered blood pressure in obese
hypertensive patients more effectively than an intervention of only potassium, magnesium, and fiber [95]. The
added success of the complete DASH diet was attributed to the intake of additional bioactive nutrients such as the
antioxidant vitamins C and E, and folate, arginine, and lycopene. Additional research is needed to further confirm
the effects of these nutrients and determine if others (i.e. phytochemicals, etc) participate in the management of
obesity-induced hypertension. Other intervention trials have demonstrated similar beneficial effects following
compliance to a DASH diet [87, 88, 96, 97]. In addition, weight loss of approximately 5% has been shown to significantly
reduce and manage the RAAS and positively contribute to reduced blood pressure [96]. Therefore, dietary
approaches to adequately manage obesity-induced hypertension should focus on proper micronutrient intake and
at least moderate weight loss.


Obesity significantly increases the incidence of NAFLD, with hepatic fat deposition (steatosis) being the primary
feature. Simple steatosis may be benign but progresses to non-alcoholic steatohepatitis (NASH) when the liver
exhibits overt inflammatory damage. NASH is now considered as one of the most common causes of terminal liver
diseases including liver cirrhosis and hepatocellular carcinoma. Due to the close relationship between obesity and
NAFLD, most dietary approaches used for obesity management are also applicable to NAFLD [98, 99]

Fat Content

It is accepted that inflammation drives the progression from simple steatosis to NASH. Accordingly, anti-inflammatory
nutritional approaches have been considered for managing NAFLD. In 2012, the Practice Guideline
by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the
American Gastroenterological Association stated that omega-3 fatty acids may be beneficial for NAFLD; although it
was not recommended to treat NAFLD [98]. Six years later, the Guideline regarding omega-3 fatty acids remains the
[99]. This guideline, interestingly, can be interpreted in either a positive or negative way. On the one hand,
there is a lack of convincing clinical evidence to consistently support the effect of omega-3 fatty acids on improving
or reserving liver histology and serum ALT [100]. On the other hand, supplementation with omega-3 fatty acids
brings about beneficial effects on NAFLD. For example, treatment with docosahexaenoic acid (DHA) plus
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eicosapentaenoic acid (EPA) for 15 -18 months is associated with a decrease in liver fat content; although the
treatment did not improve fibrosis scores [101]. Moreover, a significant number of studies using rodent models of
NAFLD have attributed the beneficial effects of omega-3 fatty acids to mechanisms varying from decreasing
hepatic inflammation [102] and suppression of liver oxidative stress [103] to attenuating the TGF?-Smad3 pathway [104]
It should be noted that omega-3 fatty acids are also beneficial to obesity-associated insulin resistance. As such, the
systemic benefits of omega-3 fatty acids are expected to also account for its anti-NAFLD effect.


During NASH, oxidative stress is viewed as a critical factor underlying the development of hepatocellular damage.
Given this, vitamin E has been used to treat NASH [105-107]. The results consistently support the effects of vitamin E
on reducing ALT and improving fibrosis scores in NASH patients. Based on convincing evidence, vitamin E has been
continuously recommended to treat non-diabetic adults with biopsy-proven NASH [98, 99]. However, vitamin E is not
recommended to treat NASH in diabetic patients, NAFLD without a liver biopsy, NASH cirrhosis, or cryptogenic
cirrhosis [98, 99]


While a number of nutrients have been considered to treat obesity-associated metabolic disease, it is worth noting
that diet composition appears to be more important in terms of generating a profound impact on health. As
supported by evidence from studies of either animal or human subjects, differences in diet composition have been
shown to alter biomarkers related to metabolic diseases varying from metabolites to lifespan [108-110]

Low Protein and High Carbohydrate Diet

The benefits of CR have been previously reviewed [5]. Interestingly, recent evidence also suggests that altering diet
composition, but not energy intake, is sufficient enough to modulate lifespan and metabolic aspects. For instance,
upon altering primarily protein and carbohydrate amount, Solon-Biet et al. demonstrated that replacing protein
with carbohydrate is capable of optimizing longevity and health in mice likely by suppressing hepatic mammalian
target of rapamycin (mTOR) [109]. A similar study in mice further indicated that low protein and high carbohydrate
diet under ad libitum conditions generates metabolic benefits comparable with those achieved by CR [110]. To be
noted, these findings were made from mice under CR or ad libitum conditions, which are different from obese or
diseased conditions. Indeed, in terms of managing metabolic diseases, high protein and low carbohydrate (HPLC)
diet, but not low protein high carbohydrate (LPHC) diet, is more beneficial. In support of this, certain studies
involving human subjects with stage 1 hypertension have shown that partial substitution of carbohydrate with
either protein or monounsaturated fat can lower blood pressure, improve lipid levels, and reduce estimated
cardiovascular risk [108]. Thus, the benefits and optimal use of HPLC vs. LPHC diet appear to be dependent on the
presence (or absence) of diseases.

High Protein and Low Carbohydrate Diet

As mentioned above, the HPLC diet is beneficial for subjects with certain health issues associated with metabolic
syndrome. This is true when the ratios of macronutrients are within a relatively balanced range. For example, a
the trial that examined the effect of altering the composition of a DASH diet indicated that each of the three diets in
which saturated fats were replaced by carbohydrate, protein, or mono-unsaturated fatty acids was able to lower
blood pressure compared with baseline [111]. In this study, the composition of carbohydrate: fat: protein is 58: 27:
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15 for the carbohydrate diet, 48: 27: 25 for the protein diet, and 48: 37: 15 for the unsaturated fat diet [111]
Similarly, the trial by Furtado et al. demonstrated that the protein diet generates the most favorable benefits on
plasma lipoprotein profile and the lowest plasma total apoB concentrations while reducing plasma levels of
triglycerides [112]. Additional to lowering blood pressure and plasma apoB levels, partially replacing carbohydrate
with unsaturated fat also improves systemic insulin sensitivity [113]. These results not only validate the benefits of
replacing saturated fats with carbohydrate, protein, and/or unsaturated fat, but also demonstrate that the protein
diet appears to be able to maximize benefits relative to the carbohydrate diet and/or unsaturated fat diet. The
underlying mechanisms by which the protein diet is superior are not clear. However, it is likely that the protein diet,
at the given diet composition, does not induce mTOR activation as does the HPLC diet [109]. Also, it cannot be ruled
out that altering diet composition likely generates distinct effects on human subjects versus laboratory mice. The
latter is normally maintained by diet with carbohydrate: fat: protein composition of 62.1: 13.2: 24.6.

Low Carbohydrate, Low Protein, and High-Fat diet

As indicated by many studies, low carbohydrate, low protein, and high-fat diets (ketogenic diet) have been
considered to manage obesity and associated problems including T2DM [114, 115]. This diet is very different from the
aforementioned diets. In the context of weight loss, a ketogenic diet appears to act through preventing an increase
in appetite, and this effect is attributable to ketosis [116]. The ketogenic diet also reduces insulin secretion. This, in turn,
favors whole body fat oxidation and contributes to weight loss [115]. The ketogenic diet also exerts a glucose-lowering
an effect, which is more pronounced than that achieved by a conventional low-calorie diet [114]. Additional to reducing
body weight and lowering glucose levels, the ketogenic diet may also benefit heart health. The latter is attributable to,
at least in part, the effect of the ketogenic diet on improving dyslipidemia and hypertension [115]
Although it displays metabolic benefits, the ketogenic diet may also cause some unwanted effects. This, indeed, is well
illustrated by a study in which the effects of standard diet, Western high-fat diet, and ketogenic diet on metabolic
aspects were examined in laboratory mice [117]. In this study, diet compositions were (carbohydrate: fat: protein)
62.1: 13.2: 24.6 for standard diet, 40.7: 40.6: 18.7 for Western diet, and 0.4: 95.1: 4.5 for ketogenic diet. As
expected, Western diet caused the greatest increase in body weight whereas the ketogenic diet caused the lowest.
Also, Western diet, at either 6 weeks or 12-week duration, caused the significant increase in body fat content.
Interestingly, mice on a ketogenic diet consumed more calories compared with mice on a chow diet or Western
diet. Clearly, these results confirmed the benefits of the ketogenic diet on managing body weight. In relation to
Western diet, the ketogenic diet is anti-lipogenic. However, over a time period of 12 weeks, the ketogenic diet caused
hepatic steatosis and inflammation, which is associated with hepatic endoplasmic reticulum stress. A similar study
using mice further indicated that long-term ketogenic diet leads to reduced ?- and ?-cell mass and failed to
produce weight loss[118]. Thus, the long-term ketogenic diet is associated with increased risk for NAFLD and T2DM.
However, neither of the two studies investigated the effect of the ketogenic diet on obese mice. Thus, additional
research is needed to examine whether a ketogenic diet produces unwanted effects in obese mice similar to those in
lean mice. Nonetheless, caution is needed when considering a ketogenic diet as a nutritional intervention,
particularly over long periods of time.


Healthy nutrition is effective in terms of managing obesity and related metabolic diseases. While much attention is
paid to the benefits achieved by altering the content of healthy nutrients, it may be time to shift the focus to diet
the composition which is likely of particular importance in managing obesity and other related metabolic diseases.
Consistently, diets with balanced nutrients that are capable of generating metabolic benefits should be considered
as the primary approach for managing obesity and metabolic disease. In addition, when using a dietary approach it
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is also important to monitor off-target effects, such as unwanted side effects, while focusing on the target goals of
weight loss and systemic metabolic benefits.


This work was supported in part by grants from the National Institutes of Health (R01DK095862 to C.W.) and the
American Diabetes Association (1-17-IBS-145 to C.W.). Also, C.W. is supported by the Hatch Program of the
National Institutes of Food and Agriculture (NIFA).


The authors have no conflicts of interest (political, personal, religious, ideological, academic, intellectual,
commercial or any other) to declare in relation to this manuscript.


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