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Nutrients and Gene Expression in Type 2 Diabetes
C H A P T E R
59 Nutrients and Gene Expression in Type 2 Diabetes Dominique Langin1,2,3,4, Nathalie Viguerie1,2,3 1
Institut National de la Sante´ et de la Recherche Me´dicale (Inserm), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; 2University of Toulouse, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, Toulouse, France; 3Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France; 4Toulouse University Hospitals, Laboratory of Clinical Biochemistry, Toulouse, France
Glossary BCAA branched-chain amino acid ChREBP carbohydrate-response element-binding protein FFA free fatty acid receptor LXR liver X receptor PPAR peroxisome proliferator-activated receptor RXR retinoid X receptor SREBP sterol-responsive element binding protein TLR Toll-like receptor
The chapter sums up current knowledge on the influence of nutrients on gene expression in type 2 diabetes, with an emphasis on human studies.
NUTRIGENOMICS AND TYPE 2 DIABETES Nutrition has a profound impact on human health, especially in the setting of metabolic diseases such as obesity and type 2 diabetes. The emergence of “omics” technologies has pushed the field forward and profoundly improved the understanding of geneenutrient interactions. In this chapter, we will focus on gene expression (i.e., transcriptomics) studies in humans. For chronic diseases such as type 2 diabetes, there is a complex interaction between environmental and genetic factors. The global surge in the prevalence of type 2 diabetes is generally considered to be caused by the rapid and widespread adoption of unhealthy lifestyle habits, including poor nutrition and lack of physical activity. Diets with highly refined sugar and saturated fat content have favored an increase in fat mass, insulin resistance,
Principles of Nutrigenetics and Nutrigenomics https://doi.org/10.1016/B978-0-12-804572-5.00059-8
and type 2 diabetes. However, the genetic susceptibility to developing the disease is high. This is exemplified by studies of different populations and ethnic groups (e.g., Greenlanders and Pima Indians), characterized by a high prevalence of diabetes. The susceptibility to developing diabetes in a given environment is highly variable. Diabetic types and progression toward complications are heterogeneous. There is also considerable variation in the response to lifestyle therapies, as well as to drugs. Personalized medicine may help in that context to improve the assessment of susceptibility to adverse lifestyle exposures, complications, and treatment response. Nutrigenomics may specifically contribute to personalized care in type 2 diabetes through the study of how food components modulate the expression of genetic information in an individual, and how an individual’s genetic makeup affects the response to nutrients and other bioactive components present in food. Type 2 diabetes features a strong heritability; there is an approximately 70% lifetime risk of developing disease when both parents are affected. Genome-wide association studies have identified common variants associated with type 2 diabetes, which in aggregate contribute to a fraction of the disease heritability. Rare variants not detected by genome-wide association studies have been hypothesized to explain the missing part. Whereas such low-frequency alleles have been identified, especially in specific populations, they do not have a major role in the predisposition to type 2 diabetes (Fuchsberger et al., 2016). Unlike monogenic
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Copyright © 2020 Elsevier Inc. All rights reserved.
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59. NUTRIENTS AND GENE EXPRESSION IN TYPE 2 DIABETES
forms, genetic testing of individuals for type 2 diabetes has little clinical relevance. The identification of geneeenvironment interactions on complex traits in humans has proven to be difficult. However, some success has been achieved in exploring the regulation of gene expression through analyses of expression quantitative trait loci. Studies on the deCODE cohort revealed that unlike blood, adipose tissue gene expression profiles were strongly associated with obesity- and diabetes-related traits. Genome-wide linkage and association mapping revealed a highly significant genetic component to adipose gene expression traits (Emilsson et al., 2008). This tissue specificity was confirmed in a multitissue transcriptomic study that identified cis and trans geneebody mass index interactions only in adipose tissue (Glastonbury et al., 2016).
MACRONUTRIENTS AND TYPE 2 DIABETES Several mechanisms, such as lipotoxicity, glucotoxicity, oxidative stress, and inflammation, have been involved in the pathogenesis of type 2 diabetes. Most of these mechanisms are directly controlled by nutrients at the transcriptional level. Nutrients or their metabolites may bind transcription factors, notably nuclear receptors, and influence the expression of genes involved in metabolic and inflammatory processes. The peroxisome proliferator-activated receptors (PPARs) superfamily is one of the most investigated groups of nutrient sensors. The three members of the family act as heterodimers with the retinoid X receptor (RXR). PPARs control both metabolism and inflammation in a variety of tissues (Gross et al., 2017). PPARa, the first PPAR to be identified, is predominantly expressed in the liver, heart, and brown adipose tissue. In the liver, it regulates various pathways of lipid and lipoprotein metabolism. There is ample evidence that PPARa is the master regulator of lipid metabolism during fasting. It is also involved in the control of cholesterol, glucose, and bile acid metabolism. In the heart, PPARa is essential for optimal substrate oxidation and lipid handling. In human brown-like adipocytes, PPARa induces fatty acid anabolic and catabolic pathways, while repressing glucose oxidation. Of the three PPARs, PPARb/d shows the widest tissue distribution and is the predominantly expressed isotype in the skeletal muscle, integrating signals from physical exercise and fasting. It has a role in skeletal muscle remodeling, with a switch from glycolytic to oxidative fiber types, an increase in the capillary-to-fiber ratio, and the formation of new myofibers. PPARg, notably the adipose tissuerestricted PPARg2 isoform, has a major role in fat cells. It is essential for adipogenesis and controls metabolism
in both energy-storing white and energy-dissipating brown adipocytes. One of the PPAR transcriptional cofactors, PPARg coactivator 1a, initially described as a metabolic regulator of adaptive thermogenesis in brown adipose tissue, has been shown to act as a nutrient sensor that is essential for controlling mitochondriogenesis, fatty acid oxidation, and hepatic gluconeogenesis. In both the liver and skeletal muscle, it has a central role in adaptation to fasting. Ligands of the three PPAR isotypes exhibit antiinflammatory properties. This nonmetabolic functions can be ascribed to the transrepression of genes of proinflammatory mediators. PPARs can also interact with other transcription factors in a manner independent of DNA-binding and modulate inflammatory pathways. With respect to nutrient control of PPARs, it is puzzling that despite years of intense work, the precise nature of endogenous ligands remains elusive. As a unifying feature of most nuclear receptors, PPARs are activated by small hydrophobic ligands. Natural ligands of PPARs include fatty acids, eicosanoids, endocannabinoids, and phospholipids derived endogenously from cellular metabolism or exogenously from dietary lipids. Most show low affinity for PPARs. The distribution of these ligands in the body and the combination in which they occur in a given cell are highly variable, as is the combination of the three PPARs in a cell nucleus. Liver X receptors (LXRs) a and b act as heterodimers with RXR. Whereas LXRb distribution is ubiquitous, LXRa is highly expressed in the liver, but it is also detected in the intestine, adipose tissue, kidneys, adrenals, and macrophages. LXRs function as intracellular cholesterol sensors and bind derivatives of cholesterol such as oxysterols. In response to nutrients, a number of genes, such as those involved in cholesterol conversion to bile acids, fatty acid synthesis, and secretion of very lowedensity lipoproteins are induced. LXRs function as a critical signaling node linking lipid metabolism, inflammation, and immune cell function. Sterol-responsive element binding proteins (SREBPs) are another family of transcription factors controlling cholesterol and lipid metabolism (Wang et al., 2015). They activate a cascade of enzymes required for endogenous cholesterol, fatty acid, triglyceride, and phospholipid synthesis. Three members of the SREBP family have been described in several mammalian species: SREBP1a and 1c, produced from a single gene, and SREBP2, from a separate gene. SREBP2 mainly controls the expression of genes involved in cholesterol biosynthesis, whereas SREBP1a and SREBP1c induce transcription of genes involved in fatty acid synthesis. Cholesterol and derivatives modulate the processing of SREBP in the endoplasmic reticulum and its nuclear translocation that allows activation of target genes. Insulin controls SREBP1c expression and thereby de novo
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MICRONUTRIENTS AND TYPE 2 DIABETES
lipogenesis (i.e., the conversion of glucose carbons into fatty acid). A complex interplay between LXRs and SREBPs exists for the control of hepatic gene expression. Together with SREBP1c, carbohydrate-response element-binding protein (ChREBP) controls de novo lipogenesis in the liver and the adipose tissue. It acts as a glucose-responsive transcription factor (Filhoulaud et al., 2013). Two isoforms of ChREBP are generated by alternative promoter use in the MLXIPL gene. Glucose posttranslationally activates ChREBPa, which induces ChREBPb, a more potent transcriptional activator. They activate transcription of target genes as heterodimers with Max-like protein X. Whereas the induction of de novo lipogenesis contributing to the development of fatty liver is often viewed as a key event in the pathogenesis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, ChREBP induction of this pathway in the adipose tissue is associated with improved insulin sensitivity and may therefore prevent the development of insulin resistance and type 2 diabetes. Amino acid regulation of gene expression occurs at distinct levels: transcriptional control, messenger RNA (mRNA) stabilization under starved conditions, and regulation of the translation rate by amino acid availability. In type 2 diabetes, branched-chain amino acids (BCAAs) deserve special attention (Bifari and Nisoli, 2017). These essential amino acids are critical nutrient signals that affect metabolism, either directly or indirectly. BCAA-rich diets have been reported to improve metabolic health, including the regulation of body weight, muscle protein synthesis, and glucose homeostasis. Paradoxically, plasma levels of BCAAs positively correlate with increasing risk of insulin resistance and type 2 diabetes in humans. The latter observation may be related to impaired BCAA catabolism. The effect of BCAAs drastically changes when they act under catabolic or anabolic conditions. In catabolic states, BCAAs can behave as energy substrates directly oxidized in the muscle or converted to gluconeogenic-ketogenic substrates. In contrast, under anabolic conditions, BCAAs stimulate protein synthesis and cell growth. Therefore, to predict their effects accurately, the overall catabolic or anabolic status of patients should be known. Besides nuclear receptors, receptors present at the cell membrane recognize nutrients and transduce intracellular signals modulating insulin signaling. Extensive research has been conducted on fatty acids. Saturated fatty acids enhance inflammatory pathways through Toll-like receptor (TLR)-dependent and independent mechanisms, thereby promoting insulin resistance (Glass and Olefsky, 2012). Bacterial lipids activate TLRs. The main TLR4 ligand is lipopolysaccharide, a lipid component of the walls of gram-negative bacteria, whereas TLR2 ligands include the lipoteichoic acid, a component of gram-positive bacteria. Hence, diet-
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induced changes in gut microbiota may modulate immune response through bacterial lipids. Several G proteinecoupled receptors, previously considered to be orphan receptors, are activated by endogenous and dietary fatty acids. As an example, the free fatty acid receptors (FFA1e4), which are expressed in various cell types including pancreatic b cells, have provided exciting new data in nutrient sensing (Miyamoto et al., 2016). FFA1-4 bind different fatty acid species. FFA2 and FFA3 are activated by short-chain fatty acids such as acetate, propionate, and butyrate, which are the primary metabolic byproducts of anaerobic fermentation by intestinal microflora. FFA1 and FFA4 are both activated by medium- and long-chain fatty acids, including the u3 polyunsaturated fatty acids, primarily a-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. u3 fatty acids produce antiinflammatory effects by stimulating FFA4, also known as GPR120, and the production of resolvins and protectins. Preclinical models show the ability of FFA4 agonists to improve glucose disposal and enhance insulin sensitivity.
MICRONUTRIENTS AND TYPE 2 DIABETES Some vitamins with direct relevance to type 2 diabetes exert effects through nuclear receptors. Vitamin A derivatives, mainly retinoic acid, regulate gene expression by activating retinoic acid receptors and RXRs (Zhang et al., 2015). Because PPARg/RXRa heterodimers can also be activated by RXR agonists, they constitute attractive candidates for the treatment of type 2 diabetes. Retinoids have been shown to modulate gene expression in several insulin-sensitive tissues, notably the liver and adipose tissue, where they have a crucial role in adipogenesis. However, there is still no clear indication for the routine recommendation of vitamin A supplements in the management of type 2 diabetes. Low vitamin D intake has been associated with a higher incidence of type 2 diabetes (Boucher, 2011). Vitamin D acts through vitamin D receptoreRXR heterodimers. It may enhance insulin sensitivity by modulating gene expression in the skeletal muscle and adipose tissue, and it affects insulin secretion by controlling calcium concentration and flux in pancreatic b cells. Metaanalyses of observational studies show an association between vitamin D status and the prevalence of glucose intolerance or type 2 diabetes. Randomized controlled trials investigating the effect of vitamin D supplementation on glucose homeostasis gave mixed results, from lack of effect to a positive impact.
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Disturbed iron homeostasis is associated with hyperglycemia and diabetes. Elevated body iron stores and serum ferritin are risk factors for type 2 diabetes (Fernandez-Real et al., 2015). The liver is the major reservoir of iron in the body. Excess iron storage in the liver interferes with glucose metabolism, causing hyperinsulinemia, with both decreased insulin extraction and impaired insulin signaling. A hyperinsulinemic status, on the other hand, favors the intrahepatic deposition of iron. Iron deficiency is associated with enhanced hepatic glucose production and increased SREBP1ccontrolled de novo lipogenesis. Iron also controls adipose tissue function both at the fat cell level, by modulating adipogenesis, and at the macrophage level, by modulating polarization and inflammatory response. Whereas key aspects of systemic iron metabolism are regulated transcriptionally (e.g., hepatic expression of hepcidin, a hormone-regulating iron fluxes and levels) and posttranslationally (e.g., function of the iron exporter ferroportin by hepcidin), cellular iron homeostasis is regulated posttranscriptionally by iron regulatory proteins. These RNA-binding proteins interact with conserved cis-regulatory hairpin structures present in the 50 - or 30 -untranslated regions of target mRNAs.
CALORIE RESTRICTION AND INSULIN RESISTANCE Calorie restriction is a standard lifestyle therapy in obesity management and prevention of type 2 diabetes. Calorie restriction-induced weight loss improves the metabolic profile of most obese individuals. In terms of transcriptomics, hypocaloric diets have been the most comprehensively studied dietary interventions; adipose tissue gene expression profiles were thoroughly investigated. Several conclusions may be drawn from those studies. First, significant changes in adipose tissue gene expression profiles were observed with very low to low-calorie diets (i.e., diets with energy intake of 3.3 MJ [800 kcal] per day to diets with an energy deficit of 2.5 MJ [600 kcal] per day less than the individually estimated daily energy requirement). Expression of metabolism genes in fat cells is decreased, whereas expression of immune genes in macrophages is increased or unchanged (Capel et al., 2009). Second, energy restriction has a much more pronounced impact on variations in human adipose tissue gene expression than macronutrient composition (Capel et al., 2008; Viguerie et al., 2012). Differences in nutrient composition are less pronounced in human studies than in most rodent studies. Third, when very lowecalorie diets are followed by weight maintenance diets, either ad libitum or isocaloric, an opposite regulation of gene expression is observed between the two phases (Capel et al., 2009;
Viguerie et al., 2012). The associations between adipose tissue gene expression and insulin sensitivity are different in the various phases of dietary interventions.
CONCLUDING REMARKS Several specificities of human nutrigenomic studies need to be considered in the field of type 2 diabetes. Unlike studies of diets in model organisms, whose compositions are often extreme, differences in human trials of nutrient composition between diets usually remain within dietary recommendations and nutritional requirements defined by the Food and Agriculture Organization of the United Nations/World Health Organization or regional and national scientific societies. In interventional studies, the number of subjects is often too low to capture moderate effects. This is also a limitation for investigating genotypee nutrient interactions and the genetic control of gene expression. Because study design and study populations are never the same, true replication is rarely achieved. Unlike drug trials, there is no placebo arm. The studies are often not blinded. Moreover, the interdependence of nutrients needs to be considered (e.g., the proportions of fat and carbohydrate, changing in parallel during hypocaloric diets). Another limitation pertains to the availability of tissues. Blood is not the most suitable tissue for investigating metabolic diseases. Tissues involved in the pathogenesis of type 2 diabetes, such as the liver, skeletal muscle, and pancreas, are rarely available, and notably so in dietary interventions, when biopsies should be performed at multiple time points. The major exception is adipose tissue. Microbiopsy of subcutaneous fat allows fast and painless adipose tissue sampling, providing enough high-quality total RNA for high-throughput quantitative polymerase chain reaction, RNA sequencing, or DNA microarray analyses (Viguerie et al., 2012). Studies on this tissue have proven highly informative in investigating the effects of calorie restriction. Most of these caveats are now being addressed. The number of participants in carefully controlled dietary interventions is increasing. In some of these trials (e.g., CALERIE and DiOGenes), consecutive collections of fat and skeletal muscle samples were adopted. Less invasive methods are becoming common for performing microbiopsies of adipose tissue, skeletal muscle, and liver. Integration of “omics” data is also a challenge that shows considerable development. Cross-talk between metabolic organs and gut microbiota is emerging as an important determinant of dietary responses and metabolic alterations (Zeevi et al., 2015). The same is occurring in epigenetic studies bridging nutrigenetics and nutrigenomics. Thus, there is promise that such developments will shed much more relevant light in this new area of science.
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REFERENCES
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59 Nutrients and Gene Expression in Type 2 Diabetes Dominique Langin1,2,3,4, Nathalie Viguerie1,2,3 1
Institut National de la Sante´ et de la Recherche Me´dicale (Inserm), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; 2University of Toulouse, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, Toulouse, France; 3Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France; 4Toulouse University Hospitals, Laboratory of Clinical Biochemistry, Toulouse, France
Glossary BCAA branched-chain amino acid ChREBP carbohydrate-response element-binding protein FFA free fatty acid receptor LXR liver X receptor PPAR peroxisome proliferator-activated receptor RXR retinoid X receptor SREBP sterol-responsive element binding protein TLR Toll-like receptor
The chapter sums up current knowledge on the influence of nutrients on gene expression in type 2 diabetes, with an emphasis on human studies.
NUTRIGENOMICS AND TYPE 2 DIABETES Nutrition has a profound impact on human health, especially in the setting of metabolic diseases such as obesity and type 2 diabetes. The emergence of “omics” technologies has pushed the field forward and profoundly improved the understanding of geneenutrient interactions. In this chapter, we will focus on gene expression (i.e., transcriptomics) studies in humans. For chronic diseases such as type 2 diabetes, there is a complex interaction between environmental and genetic factors. The global surge in the prevalence of type 2 diabetes is generally considered to be caused by the rapid and widespread adoption of unhealthy lifestyle habits, including poor nutrition and lack of physical activity. Diets with highly refined sugar and saturated fat content have favored an increase in fat mass, insulin resistance,
Principles of Nutrigenetics and Nutrigenomics https://doi.org/10.1016/B978-0-12-804572-5.00059-8
and type 2 diabetes. However, the genetic susceptibility to developing the disease is high. This is exemplified by studies of different populations and ethnic groups (e.g., Greenlanders and Pima Indians), characterized by a high prevalence of diabetes. The susceptibility to developing diabetes in a given environment is highly variable. Diabetic types and progression toward complications are heterogeneous. There is also considerable variation in the response to lifestyle therapies, as well as to drugs. Personalized medicine may help in that context to improve the assessment of susceptibility to adverse lifestyle exposures, complications, and treatment response. Nutrigenomics may specifically contribute to personalized care in type 2 diabetes through the study of how food components modulate the expression of genetic information in an individual, and how an individual’s genetic makeup affects the response to nutrients and other bioactive components present in food. Type 2 diabetes features a strong heritability; there is an approximately 70% lifetime risk of developing disease when both parents are affected. Genome-wide association studies have identified common variants associated with type 2 diabetes, which in aggregate contribute to a fraction of the disease heritability. Rare variants not detected by genome-wide association studies have been hypothesized to explain the missing part. Whereas such low-frequency alleles have been identified, especially in specific populations, they do not have a major role in the predisposition to type 2 diabetes (Fuchsberger et al., 2016). Unlike monogenic
441
Copyright © 2020 Elsevier Inc. All rights reserved.
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forms, genetic testing of individuals for type 2 diabetes has little clinical relevance. The identification of geneeenvironment interactions on complex traits in humans has proven to be difficult. However, some success has been achieved in exploring the regulation of gene expression through analyses of expression quantitative trait loci. Studies on the deCODE cohort revealed that unlike blood, adipose tissue gene expression profiles were strongly associated with obesity- and diabetes-related traits. Genome-wide linkage and association mapping revealed a highly significant genetic component to adipose gene expression traits (Emilsson et al., 2008). This tissue specificity was confirmed in a multitissue transcriptomic study that identified cis and trans geneebody mass index interactions only in adipose tissue (Glastonbury et al., 2016).
MACRONUTRIENTS AND TYPE 2 DIABETES Several mechanisms, such as lipotoxicity, glucotoxicity, oxidative stress, and inflammation, have been involved in the pathogenesis of type 2 diabetes. Most of these mechanisms are directly controlled by nutrients at the transcriptional level. Nutrients or their metabolites may bind transcription factors, notably nuclear receptors, and influence the expression of genes involved in metabolic and inflammatory processes. The peroxisome proliferator-activated receptors (PPARs) superfamily is one of the most investigated groups of nutrient sensors. The three members of the family act as heterodimers with the retinoid X receptor (RXR). PPARs control both metabolism and inflammation in a variety of tissues (Gross et al., 2017). PPARa, the first PPAR to be identified, is predominantly expressed in the liver, heart, and brown adipose tissue. In the liver, it regulates various pathways of lipid and lipoprotein metabolism. There is ample evidence that PPARa is the master regulator of lipid metabolism during fasting. It is also involved in the control of cholesterol, glucose, and bile acid metabolism. In the heart, PPARa is essential for optimal substrate oxidation and lipid handling. In human brown-like adipocytes, PPARa induces fatty acid anabolic and catabolic pathways, while repressing glucose oxidation. Of the three PPARs, PPARb/d shows the widest tissue distribution and is the predominantly expressed isotype in the skeletal muscle, integrating signals from physical exercise and fasting. It has a role in skeletal muscle remodeling, with a switch from glycolytic to oxidative fiber types, an increase in the capillary-to-fiber ratio, and the formation of new myofibers. PPARg, notably the adipose tissuerestricted PPARg2 isoform, has a major role in fat cells. It is essential for adipogenesis and controls metabolism
in both energy-storing white and energy-dissipating brown adipocytes. One of the PPAR transcriptional cofactors, PPARg coactivator 1a, initially described as a metabolic regulator of adaptive thermogenesis in brown adipose tissue, has been shown to act as a nutrient sensor that is essential for controlling mitochondriogenesis, fatty acid oxidation, and hepatic gluconeogenesis. In both the liver and skeletal muscle, it has a central role in adaptation to fasting. Ligands of the three PPAR isotypes exhibit antiinflammatory properties. This nonmetabolic functions can be ascribed to the transrepression of genes of proinflammatory mediators. PPARs can also interact with other transcription factors in a manner independent of DNA-binding and modulate inflammatory pathways. With respect to nutrient control of PPARs, it is puzzling that despite years of intense work, the precise nature of endogenous ligands remains elusive. As a unifying feature of most nuclear receptors, PPARs are activated by small hydrophobic ligands. Natural ligands of PPARs include fatty acids, eicosanoids, endocannabinoids, and phospholipids derived endogenously from cellular metabolism or exogenously from dietary lipids. Most show low affinity for PPARs. The distribution of these ligands in the body and the combination in which they occur in a given cell are highly variable, as is the combination of the three PPARs in a cell nucleus. Liver X receptors (LXRs) a and b act as heterodimers with RXR. Whereas LXRb distribution is ubiquitous, LXRa is highly expressed in the liver, but it is also detected in the intestine, adipose tissue, kidneys, adrenals, and macrophages. LXRs function as intracellular cholesterol sensors and bind derivatives of cholesterol such as oxysterols. In response to nutrients, a number of genes, such as those involved in cholesterol conversion to bile acids, fatty acid synthesis, and secretion of very lowedensity lipoproteins are induced. LXRs function as a critical signaling node linking lipid metabolism, inflammation, and immune cell function. Sterol-responsive element binding proteins (SREBPs) are another family of transcription factors controlling cholesterol and lipid metabolism (Wang et al., 2015). They activate a cascade of enzymes required for endogenous cholesterol, fatty acid, triglyceride, and phospholipid synthesis. Three members of the SREBP family have been described in several mammalian species: SREBP1a and 1c, produced from a single gene, and SREBP2, from a separate gene. SREBP2 mainly controls the expression of genes involved in cholesterol biosynthesis, whereas SREBP1a and SREBP1c induce transcription of genes involved in fatty acid synthesis. Cholesterol and derivatives modulate the processing of SREBP in the endoplasmic reticulum and its nuclear translocation that allows activation of target genes. Insulin controls SREBP1c expression and thereby de novo
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MICRONUTRIENTS AND TYPE 2 DIABETES
lipogenesis (i.e., the conversion of glucose carbons into fatty acid). A complex interplay between LXRs and SREBPs exists for the control of hepatic gene expression. Together with SREBP1c, carbohydrate-response element-binding protein (ChREBP) controls de novo lipogenesis in the liver and the adipose tissue. It acts as a glucose-responsive transcription factor (Filhoulaud et al., 2013). Two isoforms of ChREBP are generated by alternative promoter use in the MLXIPL gene. Glucose posttranslationally activates ChREBPa, which induces ChREBPb, a more potent transcriptional activator. They activate transcription of target genes as heterodimers with Max-like protein X. Whereas the induction of de novo lipogenesis contributing to the development of fatty liver is often viewed as a key event in the pathogenesis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, ChREBP induction of this pathway in the adipose tissue is associated with improved insulin sensitivity and may therefore prevent the development of insulin resistance and type 2 diabetes. Amino acid regulation of gene expression occurs at distinct levels: transcriptional control, messenger RNA (mRNA) stabilization under starved conditions, and regulation of the translation rate by amino acid availability. In type 2 diabetes, branched-chain amino acids (BCAAs) deserve special attention (Bifari and Nisoli, 2017). These essential amino acids are critical nutrient signals that affect metabolism, either directly or indirectly. BCAA-rich diets have been reported to improve metabolic health, including the regulation of body weight, muscle protein synthesis, and glucose homeostasis. Paradoxically, plasma levels of BCAAs positively correlate with increasing risk of insulin resistance and type 2 diabetes in humans. The latter observation may be related to impaired BCAA catabolism. The effect of BCAAs drastically changes when they act under catabolic or anabolic conditions. In catabolic states, BCAAs can behave as energy substrates directly oxidized in the muscle or converted to gluconeogenic-ketogenic substrates. In contrast, under anabolic conditions, BCAAs stimulate protein synthesis and cell growth. Therefore, to predict their effects accurately, the overall catabolic or anabolic status of patients should be known. Besides nuclear receptors, receptors present at the cell membrane recognize nutrients and transduce intracellular signals modulating insulin signaling. Extensive research has been conducted on fatty acids. Saturated fatty acids enhance inflammatory pathways through Toll-like receptor (TLR)-dependent and independent mechanisms, thereby promoting insulin resistance (Glass and Olefsky, 2012). Bacterial lipids activate TLRs. The main TLR4 ligand is lipopolysaccharide, a lipid component of the walls of gram-negative bacteria, whereas TLR2 ligands include the lipoteichoic acid, a component of gram-positive bacteria. Hence, diet-
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induced changes in gut microbiota may modulate immune response through bacterial lipids. Several G proteinecoupled receptors, previously considered to be orphan receptors, are activated by endogenous and dietary fatty acids. As an example, the free fatty acid receptors (FFA1e4), which are expressed in various cell types including pancreatic b cells, have provided exciting new data in nutrient sensing (Miyamoto et al., 2016). FFA1-4 bind different fatty acid species. FFA2 and FFA3 are activated by short-chain fatty acids such as acetate, propionate, and butyrate, which are the primary metabolic byproducts of anaerobic fermentation by intestinal microflora. FFA1 and FFA4 are both activated by medium- and long-chain fatty acids, including the u3 polyunsaturated fatty acids, primarily a-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. u3 fatty acids produce antiinflammatory effects by stimulating FFA4, also known as GPR120, and the production of resolvins and protectins. Preclinical models show the ability of FFA4 agonists to improve glucose disposal and enhance insulin sensitivity.
MICRONUTRIENTS AND TYPE 2 DIABETES Some vitamins with direct relevance to type 2 diabetes exert effects through nuclear receptors. Vitamin A derivatives, mainly retinoic acid, regulate gene expression by activating retinoic acid receptors and RXRs (Zhang et al., 2015). Because PPARg/RXRa heterodimers can also be activated by RXR agonists, they constitute attractive candidates for the treatment of type 2 diabetes. Retinoids have been shown to modulate gene expression in several insulin-sensitive tissues, notably the liver and adipose tissue, where they have a crucial role in adipogenesis. However, there is still no clear indication for the routine recommendation of vitamin A supplements in the management of type 2 diabetes. Low vitamin D intake has been associated with a higher incidence of type 2 diabetes (Boucher, 2011). Vitamin D acts through vitamin D receptoreRXR heterodimers. It may enhance insulin sensitivity by modulating gene expression in the skeletal muscle and adipose tissue, and it affects insulin secretion by controlling calcium concentration and flux in pancreatic b cells. Metaanalyses of observational studies show an association between vitamin D status and the prevalence of glucose intolerance or type 2 diabetes. Randomized controlled trials investigating the effect of vitamin D supplementation on glucose homeostasis gave mixed results, from lack of effect to a positive impact.
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Disturbed iron homeostasis is associated with hyperglycemia and diabetes. Elevated body iron stores and serum ferritin are risk factors for type 2 diabetes (Fernandez-Real et al., 2015). The liver is the major reservoir of iron in the body. Excess iron storage in the liver interferes with glucose metabolism, causing hyperinsulinemia, with both decreased insulin extraction and impaired insulin signaling. A hyperinsulinemic status, on the other hand, favors the intrahepatic deposition of iron. Iron deficiency is associated with enhanced hepatic glucose production and increased SREBP1ccontrolled de novo lipogenesis. Iron also controls adipose tissue function both at the fat cell level, by modulating adipogenesis, and at the macrophage level, by modulating polarization and inflammatory response. Whereas key aspects of systemic iron metabolism are regulated transcriptionally (e.g., hepatic expression of hepcidin, a hormone-regulating iron fluxes and levels) and posttranslationally (e.g., function of the iron exporter ferroportin by hepcidin), cellular iron homeostasis is regulated posttranscriptionally by iron regulatory proteins. These RNA-binding proteins interact with conserved cis-regulatory hairpin structures present in the 50 - or 30 -untranslated regions of target mRNAs.
CALORIE RESTRICTION AND INSULIN RESISTANCE Calorie restriction is a standard lifestyle therapy in obesity management and prevention of type 2 diabetes. Calorie restriction-induced weight loss improves the metabolic profile of most obese individuals. In terms of transcriptomics, hypocaloric diets have been the most comprehensively studied dietary interventions; adipose tissue gene expression profiles were thoroughly investigated. Several conclusions may be drawn from those studies. First, significant changes in adipose tissue gene expression profiles were observed with very low to low-calorie diets (i.e., diets with energy intake of 3.3 MJ [800 kcal] per day to diets with an energy deficit of 2.5 MJ [600 kcal] per day less than the individually estimated daily energy requirement). Expression of metabolism genes in fat cells is decreased, whereas expression of immune genes in macrophages is increased or unchanged (Capel et al., 2009). Second, energy restriction has a much more pronounced impact on variations in human adipose tissue gene expression than macronutrient composition (Capel et al., 2008; Viguerie et al., 2012). Differences in nutrient composition are less pronounced in human studies than in most rodent studies. Third, when very lowecalorie diets are followed by weight maintenance diets, either ad libitum or isocaloric, an opposite regulation of gene expression is observed between the two phases (Capel et al., 2009;
Viguerie et al., 2012). The associations between adipose tissue gene expression and insulin sensitivity are different in the various phases of dietary interventions.
CONCLUDING REMARKS Several specificities of human nutrigenomic studies need to be considered in the field of type 2 diabetes. Unlike studies of diets in model organisms, whose compositions are often extreme, differences in human trials of nutrient composition between diets usually remain within dietary recommendations and nutritional requirements defined by the Food and Agriculture Organization of the United Nations/World Health Organization or regional and national scientific societies. In interventional studies, the number of subjects is often too low to capture moderate effects. This is also a limitation for investigating genotypee nutrient interactions and the genetic control of gene expression. Because study design and study populations are never the same, true replication is rarely achieved. Unlike drug trials, there is no placebo arm. The studies are often not blinded. Moreover, the interdependence of nutrients needs to be considered (e.g., the proportions of fat and carbohydrate, changing in parallel during hypocaloric diets). Another limitation pertains to the availability of tissues. Blood is not the most suitable tissue for investigating metabolic diseases. Tissues involved in the pathogenesis of type 2 diabetes, such as the liver, skeletal muscle, and pancreas, are rarely available, and notably so in dietary interventions, when biopsies should be performed at multiple time points. The major exception is adipose tissue. Microbiopsy of subcutaneous fat allows fast and painless adipose tissue sampling, providing enough high-quality total RNA for high-throughput quantitative polymerase chain reaction, RNA sequencing, or DNA microarray analyses (Viguerie et al., 2012). Studies on this tissue have proven highly informative in investigating the effects of calorie restriction. Most of these caveats are now being addressed. The number of participants in carefully controlled dietary interventions is increasing. In some of these trials (e.g., CALERIE and DiOGenes), consecutive collections of fat and skeletal muscle samples were adopted. Less invasive methods are becoming common for performing microbiopsies of adipose tissue, skeletal muscle, and liver. Integration of “omics” data is also a challenge that shows considerable development. Cross-talk between metabolic organs and gut microbiota is emerging as an important determinant of dietary responses and metabolic alterations (Zeevi et al., 2015). The same is occurring in epigenetic studies bridging nutrigenetics and nutrigenomics. Thus, there is promise that such developments will shed much more relevant light in this new area of science.
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