Macronutrient-Mediated Inflammation and Oxidative Stress: Relevance to Insulin Resistance, Obesity, and Atherogenesis

Abstract

Context

The intake of macronutrients as components of a Western dietary pattern leads to oxidative stress and inflammation.

Evidence Acquisition

Data were largely retrieved from our previous and most recent work. PubMed and Google Scholar were searched for recent articles on the effect of macronutrients/dietary intake on inflammation, insulin resistance, obesity, and atherogenesis. The most relevant, high-quality articles were included in our review.

Evidence Synthesis

Our previous work has demonstrated the molecular mechanisms of macronutrient-mediated oxidative stress and inflammation. With the induction of inflammation, proinflammatory molecules potentially interfere with insulin signal transduction, thus causing insulin resistance. In addition, other molecules promote atherogenic inflammation. More recently, our work has also shown that certain foods are noninflammatory or anti-inflammatory and thus, do not interfere with insulin signaling. Finally, as obesity is induced by chronic excessive caloric intake, it is characterized by an increase in the expression of proinflammatory molecules, which are induced acutely by a Western diet. Caloric restriction, including fasting, is associated with a reduction in oxidative and inflammatory stress.

Conclusions

This review summarizes and attempts to provide an up-to-date profile of the molecular mechanisms involved in macronutrient-mediated oxidative/inflammatory stress and its potential consequences. An understanding of these underlying mechanisms is crucial for making appropriate dietary choices.

The increasing global burden of diet-related metabolic disorders, such as obesity, metabolic syndrome, type 2 diabetes and atherosclerosis, poses substantial concerns. Several dietary recommendations outline the benefits of a healthier eating habit to mitigate the effects of diet-associated health problems; however, the cellular and molecular mechanisms underlying the effects of these diets are not known. With the increased Westernization of diets across the globe, from consumption of processed foods and proliferation of fast-food restaurants, the stage is set for a host of systemic disorders that occur in tandem with the state of obesity such as type 2 diabetes, metabolic syndrome, several malignancies, and cardiovascular and gastrointestinal disorders. It has been established that the intake of macronutrients is closely associated with inflammation. Persistent, chronic, low-grade inflammation occurs in the insulin-resistant states of obesity and type 2 diabetes and the associated disorders, including atherosclerosis, seen in these conditions. An understanding of the key pathological processes involved in macronutrient-mediated inflammation and its implications for health is essential. This review highlights the mechanisms involved in macronutrient-induced inflammation and the related complications of obesity and type 2 diabetes. Adaptation of well-informed, healthier lifestyle choices might be influenced by a more thorough understanding of the role of macronutrients in these diet-related public health conditions.

Macronutrient Intake and the Obesity Epidemic

The habitual consumption of unhealthy diets is largely responsible for the global rise in obesity, diabetes, metabolic syndrome, and the atherosclerotic cardiovascular complications (1). The macronutrient composition of the diet plays an important role in the quest for food. For instance, complex nondigestible carbohydrates are slowly digested, and they enhance satiety, which is crucial to maintain caloric restriction. In contrast, high-calorie meals (from refined carbohydrates) and fatty meals are known to have a minimal satiating effect (2–4), leading to more cravings and extra caloric consumption. This sustains excessive energy intake from chronic overconsumption, which is needed for obesity to develop and to be sustained. Over time, an elevation of the set point for the body weight occurs, and this is partly responsible for the difficulty experienced in maintaining weight loss for a long period of time by individuals with obesity who successfully lose weight (5).

Macronutrients, Inflammation, and Insulin Resistance

Macronutrient-mediated oxidative stress and inflammation occur with food consumption, and they are largely dependent on the macronutrient composition of the ingested food; i.e., they are specific to certain kinds of food and are not seen with other foods (6–8). An equicaloric (300 calories) amount of glucose (75 g), lipid (33 g), or protein (75 g) challenge in normal subjects demonstrates increments in reactive oxygen species (ROS) generation, with the protein challenge demonstrating the least production of ROS (9, 10). Increased generation of superoxide, mediated by increased nicotinamide adenine dinucleotide phosphate oxidase activity, is seen, with an associated increase in the expression of p47^phox, one of its key subunits. Glucose intake also induces an increase in the activity of the major proinflammatory transcription factor, nuclear factor (NF)-κB, in the nucleus and a reduction in the expression of IkBα, its inhibitor. This results in an increase in the expression of TNF-α, a proinflammatory cytokine; monocyte chemotactic protein-1, a key chemokine; and intercellular adhesion molecule-1 (ICAM-1).

Glucose administration to nondiabetic subjects also induces other acute inflammatory changes at the cellular and molecular levels for at least 3 hours (9, 11), with more intense and prolonged effects in individuals with obesity with impaired glucose tolerance (11). Other proinflammatory transcription factors, such as activator protein-1 and intranuclear early growth response gene-1, are activated by the intake of glucose, resulting in an increased expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), plasminogen activator inhibitor-1, and tissue factor (12). This clearly demonstrates the induction of a prothrombotic state, in addition to the oxidative and inflammatory stress seen following the intake of glucose.

Cream (saturated fat) intake increases ROS generation, p47^phox expression, and plasma concentration of thiobarbituric acid-reactive species, which is an index of lipid peroxidation. In addition, cream induces an increase in intranuclear NF-κB binding, a decrease in IκBα, and an increase in the expression of proinflammatory cytokines. Plasma concentrations of IL-12 and IL-18 increased, and cream ingestion induced an increase in intracellular lipid content in mononuclear cells (MNCs) (6, 10). In addition, cream intake results in an increase in the expression of CD68 and platelet-endothelial cell adhesion molecule (PECAM) in MNCs (Fig. 1) (13). CD68 is a marker of the conversion of the monocyte into a macrophage, whereas PECAM is the key adhesion molecule facilitating the transendothelial transfer of the monocyte/macrophage from the circulation into the subendothelium to contribute the formation of the atherosclerotic plaque.

Figure 1.

Schematic representation of the effect of a high-fat high-calorie meal and cream intake on inflammation, insulin resistance, and atherosclerosis. It is noteworthy that the ingestion of cream induces the profound effects shown in this figure, laying the foundations of oxidative stress, inflammation, insulin resistance, and atherogenesis. Many of these changes are blocked by healthy food choices rich in antioxidants/fiber and can be prevented or reversed with caloric restriction and weight loss. CRP, C-reactive protein; IKKβ, IκB kinase β; IRS-1-2, insulin receptor substrate 1 and 2; JAK/STAT, Janus kinase/signal transducer and activator of transcription; LPS, lipopolysaccharide; p-IR-β, phosphorylated insulin resistance β; PTP-1B, protein tyrosine phosphatase 1B; SOCS-3, suppressor of cytokine signaling 3; TLRs, Toll-like receptors.

On the basis of the above data on glucose and cream, the effect of a popular brand of a fast-food restaurant’s high-fat high-calorie (HFHC) meal was investigated (Fig. 1). This 910-calorie HFHC meal increases p47^phox expression and ROS generation (14). The transcription factor NF-κB is activated via the induction of IκB kinase (IKK) and the phosphorylation of IκBα (15). Elevated levels of TNF-α, IL-1β, plasma endotoxin, and Toll-like receptor (TLR)-4 expression and its coreceptor CD-14 were induced. Suppressor of cytokine signaling 3 (SOCS-3) and IKKβ, which with TNF-α, interfere with insulin signal transduction at the insulin receptor substrate 1 (IRS-1) level, are induced after the intake of these meals (6, 16). TNF-α plays a key role in insulin resistance via the suppression of the autophosphorylation of the tyrosine residue of the insulin receptor and the suppression of IRS-1 phosphorylation, thus, resulting in the inhibition of insulin-stimulated glucose uptake (17). IL-1β is a key cytokine mediating damage to the β-cell, whereas SOCS-3 causes ubiquitylation and proteolysis of IRS-1 (18). The habitual consumption of these meals results in caloric overload, obesity, and insulin resistance. SOCS-3 also interferes with leptin signaling, which could result in lack of satiety and potentiate an increase in caloric intake (19). Progressive weight gain occurs with insulin resistance, predisposing to hypertension, hypertriglyceridemia, the metabolic syndrome, and a host of systemic complications. Increased malondialdehyde levels (an index of lipid peroxidation and oxidative stress) are also seen after the ingestion of HFHC meals (16). The supraphysiologic postprandial glycemia and lipidemia that occur following the ingestion of these meals potentiate inflammatory and oxidative stress, and these are indicators of future cardiovascular events (20). Elevated plasma concentrations of inflammatory mediators significantly increase the risk of atherosclerotic complications. In contrast to the proinflammatory effects of HFHC meals, the intake of equicaloric meals rich in fruit and fiber do not induce an increase in ROS generation or inflammation at the cellular and molecular level (7, 14, 21). Similar to our findings on macronutrient-induced inflammation, Nappo et al. (22) described substantial increments in proinflammatory mediators, such as IL-6, TNF-α, ICAM-1, and vascular cell adhesion molecule-1, following a high-fat meal (760 Kcal) in both healthy and diabetic individuals. However, the study by Nappo et al. (22) in healthy subjects did not show a substantial rise in these indices following an isoenergetic carbohydrate meal. Whereas adequate production of insulin may partly account for this observation, a closer scrutiny of the carbohydrate meal ingested by these subjects revealed 4.5 g of fiber and 60 g of tomatoes. It is quite possible then that the anti-inflammatory effect of fiber coupled with the polyphenols and antioxidants in tomatoes may have attenuated the inflammatory effect of the carbohydrate meal in the healthy subjects. In accordance with this observation is the study by Esposito et al. (23) who demonstrated a fall in the baseline serum levels of IL-18 in both diabetic and nondiabetic subjects who ingested a high-carbohydrate, high-fiber meal. It is also worth mentioning that in the study by van Oostrom et al. (24) in healthy, subjects without obesity, fat and glucose resulted in increased neutrophilia, with fat resulting in a substantial increase in IL-6. This is further buttressed by the fact that IL-6 gene expression and IL-6 protein synthesis/secretion by skeletal muscle are shown to be induced by saturated free fatty acids, such as palmitate, whereas unsaturated fatty acids do not exert this effect (25). In fact, the polyunsaturated fatty acid (PUFA) linoleate was observed to inhibit the palmitate-induced IL-6 production.

Thus, as expounded above, HFHC meals are important in the pathogenesis of the proinflammatory states of insulin resistance, obesity, and type 2 diabetes. On the contrary, fiber-rich meals exert anti-inflammatory effects that can significantly suppress the inflammation caused by HFHC meals when these meals are compared (21). HFHC intake predisposes to visceral adiposity and intrahepatic fat accumulation, creating the milieu for inflammation, which leads to insulin resistance. Intrahepatic fat accumulation, which is even more strongly correlated to the metabolic derangements associated with obesity compared with visceral adiposity (26), is seen in 75% of type 2 diabetic patients (27). In addition, central adiposity increases with advancing age, and the importance of a healthy diet with the appropriate macronutrient composition, caloric restriction, and increased physical activity cannot be overemphasized (28). Central adiposity is closely associated with metabolic syndrome, insulin resistance, type 2 diabetes, hypogonadotropic hypogonadism, and cardiovascular diseases (29).

Obesity and Type 2 Diabetes Are Proinflammatory, Insulin-Resistant States

The proinflammatory effects of macronutrients, such as HFHC meals, are more prolonged and more intense in individuals with obesity (30), consistent with the previously established fact that the state of obesity is proinflammatory (31). Furthermore, the redox environment of the muscle is highly sensitive to macronutrients, and it shifts to a more oxidized redox state in response to high-caloric food ingestion. The overall cellular redox environment is modulated by the rate of mitochondrial emission of H₂O₂ (a gauge of mitochondrial function). Mitochondrial H₂O₂ emission has been demonstrated to be acutely increased in lean subjects following a fatty meal, with substantial reductions in the ratio of reduced glutathione (GSH) to oxidized GSH disulfide (GSSG) (32). A more pronounced effect is seen in those with obesity, with greater increments in mitochondrial H₂O₂ emission, and further reductions in GSH/GSSG and cellular GSH content in the skeletal muscle (32). Body mass index (BMI) and homeostatic model assessment for insulin resistance were demonstrated to be negatively correlated to the GSH/GSSG ratio (32). The shift to a more oxidized redox state results in the activation of transcription factors, such as NF-κB, which induce TNF-α with consequent interference with the insulin signal transduction at the level of IRS-1. The expression of SOCS-3 is also increased, consistent with the induction of this gene, following the intake of a high-fat meal (33). The binding of IκBα to NF-κB is normally required for the prevention of the nuclear translocation of NF-κB. Oxidative stress increases phosphorylation of IκBα, leading to the dissociation of IκBα from NF-κB. This results in the translocation of NF-κB into the nucleus, activating the transcription of proinflammatory genes, including TNF-α (34). Elevated levels of TNF-α concentrations are seen in subjects with obesity (35), and the concentrations of TNF-α in the sera and adipose tissue of subjects with obesity fall with weight loss (36, 37). In addition, elevations in the plasma concentrations of products of lipid peroxidation (thiobarbituric acid-reactive species and 9- and 13-hydroxyoctadecadienoic acid) and protein carbonylation (ortho- and meta-tyrosine) are seen in those with obesity in the fasting state. Dietary restriction leads to a reduction in their levels (30, 38).

Increased mitochondrial biogenesis and fatty acid oxidation are initially seen in skeletal muscles following acute ingestion of HFHC foods. Excess fat builds up in muscle tissue as intramyocellular lipid metabolites when fatty acid supply exceeds metabolic demand. The intramyocellular lipid metabolites activate protein kinase C (39). The activation of protein kinase C subsequently results in impaired insulin signaling and decreased insulin sensitivity (40, 41). Reduced overall sensitivity of the body to insulin and decreased mitochondrial function in skeletal muscle are well documented in obesity and aging (32).

The state of insulin resistance further potentiates the inflammation seen in obesity and type 2 diabetes secondary to the reduced anti-inflammatory effect of insulin in these conditions. Insulin exerts anti-inflammatory and vasodilatory actions, and this has been demonstrated at the cellular and molecular levels (42–45). The infusion of a low dose of insulin decreases ROS generation by MNC. IκBα expression is induced, and the suppression of p47^phox expression, intranuclear NF-κB binding, TNF-α, and IL-1β is seen. Insulin suppressed plasma ICAM-1, monocyte chemotactic protein-1, early growth response gene-1, MMP-9, tissue factor, and plasminogen activator inhibitor-1 levels (42, 44). The expression of the series of TLRs (TLR-1, TLR-2, TLR-4, TLR-7, TLR-9) and PU.1 (the transcription factor responsible for their transcription) is suppressed by insulin (46). Furthermore, endothelial nitric oxide (NO) synthase and the secretion of nitric oxide (NO) from the endothelium occur with insulin administration (47). Insulin is, thus, a vasodilator at the arterial, microvascular, and venous levels (48–50). This action of insulin is appropriate for the distribution and uptake of macronutrients postprandially at the tissue level. The anti-inflammatory action of insulin is relevant to postprandial inflammation, as endotoxemia and TLR-4 induction are a part of HFHC-induced inflammatory changes. The suppression of endotoxin-induced inflammation has also been demonstrated with insulin (51). This involves the inhibition of ROS generation, lipid peroxidation, NO generation through inducible NO synthase, and macrophage migration inhibitory factor. In addition, insulin suppresses an endotoxin-induced increase in troponin I as well (unpublished observation).

In obese and diabetic patients, insulin suppresses the expression and plasma concentrations of high-mobility group box-1, which functions as a proinflammatory cytokine when secreted by damaged cells through its binding to the advanced glycation end-product receptor (51–53). Insulin also suppresses proinflammatory serine kinases, which interfere with insulin signaling via serine phosphorylation of IRS-1, and insulin decreases plasma free fatty acid concentration and lipolysis, thus, potentially increasing insulin sensitivity (52, 54). Insulin regulates the distribution, uptake, and storage of macronutrients postprandially and also modulates postprandial oxidative and inflammatory stress. However, the magnitude of postprandial oxidative and inflammatory stress and endotoxemia, generated after the intake of HFHC meals, overwhelms the suppressive action of insulin (14). Therefore, the prolonged, excessive consumption of the wrong choice of macronutrients would eventually result in insulin resistance.

The typical Western diet is rich in refined carbohydrates, saturated fat, and animal protein. Increased production of a highly atherogenic compound, trimethylamine-N-oxide, is seen with these diets rich in animal products, especially red meats (55, 56). Healthy dietary habits coupled with the partial substitution of starchy foods and red meats with foods high in plant protein and unsaturated fat are associated with positive cardiometabolic outcomes (57, 58).

Effective Intervention Strategies

Strategies to deal with the rising prevalence of obesity and its attending complications would involve disciplined lifestyle interventions, such as the choice of appropriate foods (Fig. 2) and healthy dietary patterns, caloric restriction, increased physical activity, and effective weight loss and weight maintenance strategies in the overweight/obese population.

Figure 2.

Inflammatory and noninflammatory foods (7, 59, 60).

Anti-inflammatory foods

Diets high in polyphenols and flavonoids (abundant in several fruits, vegetables, and legumes) are anti-inflammatory and thus, potentially anti-atherogenic (59, 61–64). Fresh orange juice consumption has been demonstrated to be noninflammatory on its own and to be anti-inflammatory when consumed with an HFHC meal. In spite of its caloric content being entirely a result of glucose, fructose, and sucrose, orange juice is noninflammatory, largely because of its two major flavonoids: naringenin and hesperidin. These flavonoids probably also contribute to the ability of orange juice to inhibit ROS generation, NF-κB binding, proinflammatory cytokine expression, endotoxemia, and TLR-4 expression, induced by an HFHC meal (Fig. 1) (7).

A combination of resveratrol with muscadyne grape extracts has also been shown to inhibit oxidative and inflammatory stress induced by the HFHC meal. This combination, in addition, prevented the fall in the antioxidant-enhancing transcription factor, Nrf-2, and suppressed the increase in its inhibitor, Keap-1, which is induced by HFHC meals. Nrf-2 acts through antioxidant response elements and modulates the expression of key antioxidant enzymes NQO-1, HO-1, and GSTP-1. A fall in the expression of key antioxidant enzymes NQO-1, HO-1, and GSTP-1, observed after an HFHC meal, was also prevented by the combination of resveratrol and muscadyne grapes (59).

Most recently, the addition of fiber to the HFHC meal was comprehensively shown not only to prevent oxidative stress and inflammation but also to increase insulinogenesis after the meal and reduce the glycemic increase (21). Dietary fiber also reduces endotoxemia and the induction of TLR-4 and TLR-2, the receptors for endotoxin and gram-positive bacterial products, respectively. Fiber induces reductions in the expression of proinflammatory cytokines, such as TNF-α and IL-1β, which significantly increase following an HFHC meal (7, 21). Whereas TNF-α interferes with insulin signaling, IL-1β is toxic to the β-cell. The induction of SOCS-3, the mediator of insulin resistance, was also prevented by the addition of fiber. Thus, energy-dense foods should be substituted with foods rich in fiber, such as fruits, vegetables, legumes, whole grains, etc. The benefits of fiber-rich foods have been clearly demonstrated in relation to prevention of type 2 diabetes and atherosclerosis. There are additional secondary effects of fiber supplementation. The fermentation of fiber generates short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate, which have immense beneficial effects on inflammation-mediated processes and metabolic risk factors (Fig. 3). The SCFAs activate free fatty acid receptors (FFARs), which are mainly expressed in intestinal L cells. Acetate and propionate primarily activate FFAR2, whereas FFAR3 is more often activated by propionate and butyrate (65). The release of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) is stimulated by FFAR2 and FFAR3, and this leads to improved insulin secretion. GLP-1 and PYY expression is decreased in diet-related conditions, such as type 2 diabetes (66). A study demonstrated the effects of targeted delivery of propionate to the colon via the daily administration of 10 g inulin-propionate ester (which results in a 2.5-fold increase in daily colonic propionate production) to the treatment group and 10 g inulin to the control group (67). Acute supplementation with inulin-propionate ester reduced food intake significantly from 1175 kcal to 1013 kcal (P < 0.01), a mean reduction of 13.8%. A substantial release of gut PYY and GLP-1 from human colonic cells was seen with propionate administration. Acute ingestion of 10 g inulin-propionate ester increased postprandial plasma concentrations of PYY and GLP-1 significantly. Long-term administration of propionate over 24 weeks resulted in considerable reductions in intra-abdominal adipose tissue, intrahepatocellular lipid content, and weight gain. It also prevented the deterioration in insulin sensitivity observed in the inulin-control group. Substantial reductions in low-density lipoprotein cholesterol (LDL-C; P < 0.001) and aspartate transaminase (P = 0.007) were also observed within the propionate ester group. Some of the metabolic benefits derived from SCFAs are also a result of their role in the control of energy homeostasis. Butyrate and propionate activate intestinal gluconeogenesis gene expression, thus regulating energy homeostasis. The activation of FFAR3 by the SCFAs, such as propionate, also promotes sympathetic activity, and this enhances energy expenditure (68).

Figure 3.

Schematic representation of some of the effects of dietary fiber, Western diet, and bariatric surgery on oxidative and inflammatory stress. GLP1, glucagon-like peptide 1; PPAR γ, peroxisome proliferator-activated receptor γ; PYY, peptide YY. TMAO, trimethylamine-N-oxide.

A diet high in n-6 PUFAs, which is found in abundance in plant oils, seeds, and nuts, has also been shown to decrease abdominal fat, intrahepatic fat accumulation, and peripheral insulin resistance, decreasing cardiometabolic risk factors when compared with a diet high in saturated fatty acids (58) (Table 1). PUFAs reduce serum concentrations of proprotein convertase subtilisin/kexin type 9, a key enzyme involved in the regulation of plasma LDL-C. Proprotein convertase subtilisin/kexin type 9 modulates the degradation of LDL receptors; hence, the reduction seen in LDL-C with high PUFA diets.

Table 1.

A Summary of the Cardiometabolic Outcomes of Different Dietary Interventions

Study Design	Dietary Intervention	Summary of Cardiometabolic Outcomes
Systematic review/meta-analysis (69–71)	High-fiber diet	↓ HbA1c; ↑ insulin sensitivity; ↓ fasting insulin; ↓ body weight/weight gain; ↓ fasting plasma glucose; ↓ LDL-C; ↓ total cholesterol; ↓ triglyceride; ↓ blood pressure
Meta-analysis (62)	Flavonoid-rich diet	↓ Fasting plasma glucose; ↓ total cholesterol; ↓ LDL-C; ↓ triglyceride; ↑ HDL-C; ↓ blood pressure
Randomized trial (58, 72)	PUFA-rich diet	↓ Liver fat; ↓ abdominal fat; ↑ insulin sensitivity; ↓ LDL-C
Randomized trial (73)	Calorie-restricted diet	↓ Weight; ↓ visceral and abdominal adiposity; ↓ HOMA-IR; ↓ total cholesterol; ↓ LDL-C; ↓ blood pressure

Abbreviations: HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment for insulin resistance.

Caloric restriction

Caloric restriction is crucial to sustain an ideal weight, as prolonged overconsumption of food stored as excess fat can result in obesity (74). Furthermore, adults progressively gain weight through middle age (67); hence, caloric restriction is essential to maintain energy balance to compensate for this effect. The decrease of total energy intake by avoidance of energy-dense foods from highly refined carbohydrates and fatty meals from fast foods, a reduction in total alcohol intake, and an increase in water intake has been shown to help in weight maintenance (74). Calorie-restricted diets help achieve weight loss, with improvements seen in inflammatory and oxidative stress, insulin sensitivity, glucose and lipid metabolism, blood pressure, and cardiac function (28, 38, 75) (Table 1). A significant decrease of >50% in ROS generated by polymorphonuclear leukocytes and MNC has been demonstrated following caloric restriction and weight loss in those with obesity over a period of 4 weeks, with marked reductions in the indices of lipid peroxidation, in addition to a fall in other indicators of oxidative damage, such as ortho-tyrosine and meta-tyrosine (38). A reversal of these effects occurred following cessation of caloric restriction, with ROS generation noted to exceed the initial baseline value before commencement of the dietary restriction. A similar observation was noted in normal subjects following restriction of macronutrient intake, which was achieved by a 24- and 48-hour fast. A marked and rapid reduction in ROS generation (>50%) and p47^phox expression was seen (76). Clearly, therefore, macronutrient intake is a major modulator of oxidative stress and inflammation. Interestingly, evolving evidence suggests that Sirtuin 1 (SIRT1), a mammalian nicotinamide adenine dinucleotide dependent deacetylase enzyme, is required for some of the key metabolic alterations seen with caloric restrictions. Increments in cellular and tissue expression of SIRT1 in mice studies following dietary restriction have been documented, with SIRT1 protecting against high-fat diet-induced inflammation and obesity (77). Activation of SIRT1 in some mammals is shown to substantially increase mitochondrial biogenesis in skeletal muscle and brown adipose tissue with a resultant increase in energy expenditure and protection against diet-induced weight gain (77). This is consistent with the observation that decreased SIRT1 transcription is seen in the visceral adipose tissue of morbidly patients with obesity who have severe hepatic steatosis (78). It is also of interest that compounds, such as resveratrol, have been shown to activate SIRT1 in mice (79), protecting against diet-induced metabolic disorders. However, pivotal human studies are needed in this growing field.

Bariatric surgery

Subjects with obesity with body mass index ≥ 40 kg/m² or body mass index ≥ 35 kg/m² and obesity-related comorbidities, who are unable to achieve weight loss successfully, should consider surgical weight-loss options (80). Bariatric surgery has numerous cardiometabolic benefits. Clinically apparent resolution of insulin resistance and type 2 diabetes is seen following procedures, such as Roux-en-Y gastric bypass, even before substantial weight loss occurs. This is partly attributable to the marked reductions in caloric intake (81), coupled with the reductions in mediators of oxidative and inflammatory stress. Thus, there is a reduction in ROS generation, proinflammatory cytokines, endotoxemia, and the expression of TLR-4 and SOCS-3 (82). These changes contribute to improved insulin signalin and thus, a reduction in insulin resistance. An interesting contribution from the data obtained from bariatric surgery is the reversal of complications related to morbid obesity and the underlying mechanisms. A recent study has also shown that the expression of genes and factors related to bronchial asthma is increased in the morbidly obese and that following bariatric surgery and weight loss, there is a reduction in asthma-related factors and genes (83). This is consistent with the clinical observation that there is an increase in the prevalence of asthma in such patients and that following weight loss, there is a substantial reduction in respiratory symptoms. Likewise, genes related to Alzheimer’s disease have been shown to be reduced following bariatric surgery (84). Again, it is known that the incidence of Alzheimer’s disease is increased in obesity and type 2 diabetes, and insulin resistance in the brain may be a contributing factor to its pathogenesis. Most recently, it has also been shown that bariatric surgery leads to a decrease in vasoconstrictors and an increase in vasodilators, thus contributing to a fall in blood pressure. Bariatric surgery also leads to a fall in neprilysin, which increases the risk of congestive heart failure in these patients (85). Whereas a single meal may not induce changes in these genes, it is possible that persistent intake of HFHC meals may lead to an increased expression of these genes, in addition to the proinflammatory genes known to increase following such meals.

The restructuring of the gut following bariatric surgery also leads to changes in gut microbiota, with a resultant increase in the microbial production of the SCFAs (Fig. 3). This may also contribute to reduced adiposity, weight loss, increased insulin sensitivity, and several other beneficial cardiometabolic effects (86).

Conclusion

Macronutrient intake has important implications for health. A fast food-based Western diet is clearly associated with oxidative and inflammatory stress. These lead to insulin resistance and obesity, with increased atherogenicity and cardiovascular risk factors. These risks can be avoided by the restriction of caloric intake and the choice of an appropriate diet, including fiber-rich meals, such as fresh fruits and vegetables.

Additional Information

Disclosure Summary: P.D. has received research support from National Institutes of Health, Juvenile Diabetes Research Foundation, American Diabetes Association, Novo Nordisk, Bristol Meyer Squibb, AbbVie Pharmaceuticals, Astra Zeneca, and Boehringer Ingelheim Pharmaceuticals. P.D. has received honoraria from Eli Lilly, Novartis, GlaxoSmithKline, Merck, Novo Nordisk, Takeda, and Sanofi-Adventis. The remaining authors have nothing to disclose.

Data Availability: All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.

Abbreviations:

Abbreviations:
 
• FFAR

  free fatty acid receptor

 
• GLP-1

  glucagon-like peptide 1

 
• GSH

  glutathione

 
• GSSG

  oxidized glutathione disulfide

 
• HFHC

  high-fat high-calorie

 
• ICAM-1

  intercellular adhesion molecule-1

 
• IκBα

  phosphorylation of IκBα

 
• IKK

  IκB kinase

 
• IRS-1

  insulin receptor substrate 1

 
• LDL-C

  low-density lipoprotein cholesterol

 
• MMP

  matrix metalloproteinase

 
• MNC

  mononuclear cell

 
• NF

  nuclear factor

 
• NO

  nitric oxide

 
• PECAM

  platelet-endothelial cell adhesion molecule

 
• PUFA

  polyunsaturated fatty acid

 
• PYY

  peptide YY

 
• ROS

  reactive oxygen species

 
• SCFA

  short-chain fatty acids

 
• SIRT1

  Sirtuin 1

 
• SOCS-3

  suppressor of cytokine signaling 3

 
• TLR

  Toll-like receptor