Naima Moustaid-Moussa - Academia.edu (original) (raw)

Papers by Naima Moustaid-Moussa

Cell Death & Disease

Metabolic syndrome (MetS) is a complex, emerging epidemic which disrupts the metabolic homeostasi... more Metabolic syndrome (MetS) is a complex, emerging epidemic which disrupts the metabolic homeostasis of several organs, including liver, heart, pancreas, and adipose tissue. While studies have been conducted in these research areas, the pathogenesis and mechanisms of MetS remain debatable. Lines of evidence show that physiological systems, such as the renin–angiotensin system (RAS) and autophagy play vital regulatory roles in MetS. RAS is a pivotal system known for controlling blood pressure and fluid balance, whereas autophagy is involved in the degradation and recycling of cellular components, including proteins. Although RAS is activated in MetS, the interrelationship between RAS and autophagy varies in glucose homeostatic organs and their cross talk is poorly understood. Interestingly, autophagy is attenuated in the liver during MetS, whereas autophagic activity is induced in adipose tissue during MetS, indicating tissue-specific discordant roles. We discuss in vivo and in vitro s...

Advances in Nutrition: An International Review Journal, 2011

Obesity is associated with the metabolic syndrome, a significant risk factor for developing type ... more Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid-mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet-induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health. Adv. Nutr. 2: 304-316, 2011.

Journal of Nutrition, 2014

Background: Obesity is associated with an overexpansion of adipose tissue, along with increases i... more Background: Obesity is associated with an overexpansion of adipose tissue, along with increases in blood pressure, glycemia, inflammation, and thrombosis. Research to develop nutritional interventions to prevent or treat obesity and its associated diseases is greatly needed. Previously, we demonstrated the ability of eicosapentaenoic acid (EPA) to prevent high-fat (HF) diet-induced obesity, insulin resistance, and inflammation in mice.

Advances in Nutrition: An International Review Journal, 2014

Metabolic pathways are tightly regulated in a tissue-specific manner to maintain whole-body homeo... more Metabolic pathways are tightly regulated in a tissue-specific manner to maintain whole-body homeostasis. Nutrients and hormones control these pathways at the level of transcription, translation, and/or post-translation. Genomic and proteomic tools have been predominantly used to understand metabolic regulation, and only a few studies used metabolomics approaches. Metabolomics is a powerful, unbiased approach that allows comprehensive metabolic analysis of physiologic measurements and energy balance. Thus, nutrimetabolomics can expedite our ability to identify metabolic diseases that are influenced by nutrients and to develop targeted diet-based treatments. Presentations at this symposium reviewed current resources and platforms for metabolic profiling along with statistical and bioinformatics tools for data and pathway analyses. Specific applications of metabolomics were illustrated in nutritional and disease conditions, including polycystic ovary syndrome, diabetes, and obesity and in host-gut microbiome interactions. Adv Nutr 2014;5:792-794.

Bouchard/Genetic and Molecular Aspects of Sport Performance, 2010

Regular physical activity is associated with longevity (Landi et al., 2008; Lanza et al., 2008) a... more Regular physical activity is associated with longevity (Landi et al., 2008; Lanza et al., 2008) and a lowered risk for obesity (Healy et al., 2008) and chronic diseases such as cardiovascular disease (Richardson et al., 2004), type 2 diabetes mellitus (Hu et al., 2004; Jeon et al., 2007), and site-specific cancers such as breast and colon cancer (Irwin et al., 2008; Slattery et al., 1997). Although regular physical activity is inversely associated with obesity, several studies have shown that the beneficial effects of physical activity in terms ...

Frontiers in endocrinology, 2013

Over a third of the US population is obese and at high risk for developing type 2 diabetes, insul... more Over a third of the US population is obese and at high risk for developing type 2 diabetes, insulin resistance, and other metabolic disorders. Obesity is considered a chronic lowgrade inflammatory condition that is primarily attributed to expansion and inflammation of adipose tissues. Indeed, adipocytes produce and secrete numerous proinflammatory and anti-inflammatory cytokines known as adipokines. When the balance of these adipokines is shifted toward higher production of proinflammatory factors, local inflammation within adipose tissues and subsequently systemic inflammation occur. These adipokines including leptin, visfatin, resistin, apelin, vaspin, and retinol binding protein-4 can regulate inflammatory responses and contribute to the pathogenesis of diabetes.These effects are mediated by key inflammatory signaling molecules including activated serine kinases such as c-Jun N-terminal kinase and serine kinases inhibitor κB kinase and insulin signaling molecules including insulin receptor substrates, protein kinase B (PKB, also known as Akt), and nuclear factor kappa B. Bariatric surgery can decrease body weight and improve insulin resistance in morbidly obese subjects. However, despite reports suggesting reduced inflammation and weight-independent effects of bariatric surgery on glucose metabolism, mechanisms behind such improvements are not yet well understood. This review article focuses on some of these novel adipokines and discusses their changes after bariatric surgery and their relationship to insulin resistance, fat mass, inflammation, and glucose homeostasis.

Nutrition research (New York, N.Y.), 2013

Inflammation is a major contributor to the development of atherosclerotic plaque, yet the involve... more Inflammation is a major contributor to the development of atherosclerotic plaque, yet the involvement of liver and visceral adipose tissue inflammatory status in atherosclerotic lesion development has yet to be fully elucidated. We hypothesized that an atherogenic diet would increase inflammatory response and lipid accumulation in the liver and gonadal adipose tissue (GAT) and would correlate with systemic inflammation and aortic lesion formation in low-density lipoprotein (LDL) receptor null (LDLr−/−) mice. For 32 weeks, LDLr −/− mice (n = 10/group) were fed either an atherogenic (high saturated fat and cholesterol) or control (low fat and cholesterol) diet. Hepatic and GAT lipid content and expression of inflammatory factors were measured using standard procedures. Compared with the control diet, the atherogenic diet significantly increased hepatic triglyceride and total cholesterol (TC), primarily esterified cholesterol, and GAT triglyceride content. These changes were accompanied by increased expression of acyl-CoA synthetase long-chain family member 5, CD36, ATP-binding cassette, subfamily A, member 1 and scavenger receptor B class 1, and they decreased the expression of cytochrome P450, family 7 and subfamily a, polypeptide 1 in GAT. Aortic TC content was positively associated with hepatic TC, triglyceride, and GAT triglyceride contents as well as plasma interleukin 6 and monocyte chemoattractant protein-1 concentrations. Although when compared with the control diet, the atherogenic diet increased hepatic tumor necrosis factor α production, they were not associated with aortic TC content. These data suggest that the LDLr−/− mice responded to

Stearoyl-CoA Desaturase Genes in Lipid Metabolism, 2013

ABSTRACT Macrophages are key members of the innate immune system. More recently, a preponderance ... more ABSTRACT Macrophages are key members of the innate immune system. More recently, a preponderance of evidence suggest that macrophages play an important role in metabolic homeostasis. They are implicated in the pathogenesis of metabolic disorders such as type-2 diabetes and atherosclerosis. Human macrophages express SCD1, while rodent ones express both SCD1 and SCD2. Only a few studies have investigated the regulation of SCD1 expression in macrophages and reported that nuclear transcription factors regulate its expression. Of these, liver X receptor and retinoid X receptor increase SCD1 expression, while CCAAT-/enhancer-binding protein beta, farnesoid-X-receptor, and peroxisome proliferator-activated receptor gamma suppress it. Similar to its regulation in other tissues, stearoyl-CoA desaturase (SCD) expression in macrophages is repressed by polyunsaturated fatty acids (PUFA), especially omega-3 PUFA, via nuclear receptors. Lipid-laden macrophages, known as macrophage-derived foam cells, characterize the atherosclerotic lesion. Cholesterol efflux from these foam cells, especially via ATP-binding cassette transporter A1 (ABCA1), provides protection against the cholesterol accumulation in foam cells and further progression of the atherosclerotic plaque. Increased expression of SCD destabilizes ABCA1 and reduces cholesterol efflux in macrophages. Omega-3 PUFA can increase cholesterol efflux from foam cells through inhibition of SCD1. However, SCD inhibition in saturated fat-fed animals promotes, rather than suppresses, atherosclerosis in mouse models with hypercholesterolemia. This is attributed to the proinflammatory environment induced by saturated fatty acid-mediated toll-like receptor 4 activation in these models. Fish oil can ameliorate inflammatory responses and the atherosclerotic lesion development caused by SCD1 inhibition. Overall, the exact roles and mechanisms of SCD in modulating macrophage cholesterol efflux and atherosclerosis merit further investigation.

Nutrition and Disease Prevention, 2004

Nutrition and Disease Prevention, 2004

The Journal of nutrition, 2004

Despite its potential importance in obesity and related disorders, little is known about regulati... more Despite its potential importance in obesity and related disorders, little is known about regulation of lipogenesis in human adipose tissue. To investigate this area at the molecular and mechanistic levels, we studied lipogenesis and the regulation of 1 of its core enzymes, fatty acid synthase (FAS), in human adipose tissue in response to hormonal and nutritional manipulation. As a paradigm for lipogenic genes, we cloned the upstream region of the human FAS gene, compared its sequence to that of FAS orthologs from other species, and identified important regulatory elements that lie upstream of the FAS coding region. Lipogenesis, as assessed by glucose incorporation into lipids, was increased by insulin and more so by the combination of insulin and dexamethasone (Dex, a potent glucocorticoid analogue). In parallel, FAS expression, activity, and gene transcription rate were also significantly increased by these treatments. We also showed that linoleic acid, a representative PUFA, attenuated the actions of insulin and Dex on fatty acid and lipid synthesis as well as FAS activity and expression. Using reporter assays, we determined that the regions responsible for hormonal regulation of the FAS gene lie in the proximal portion of the gene's 5'-flanking region, within which we identified an insulin response element similar to the E-box sequence we identified previously in the rat FAS gene. In summary, we demonstrated that lipogenesis occurs in human adipose tissue and can be induced by insulin, further enhanced by glucocorticoids, and suppressed by PUFA in a hormone-dependent manner.

Advances in Nutrition: An International Review Journal, 2013

Nutrients exert potent effects on metabolism through a variety of regulatory mechanisms, resultin... more Nutrients exert potent effects on metabolism through a variety of regulatory mechanisms, resulting in local and systemic changes in metabolite levels. Numerous studies have focused on mechanisms by which nutrients and disease states regulate metabolism at the gene or protein levels using genomic and proteomic approaches, respectively. However, few studies have investigated nutritional regulation of the whole metabolome. Thus, metabolomic approaches have recently emerged to complement the genomics and proteomics research and to help identify biologically meaningful metabolites and metabolic networks that control cellular responses to genetic and environmental factors, including diet, and to identify metabolic diseases that are influenced by genetic and dietary factors. These large-scale studies expedite our ability to develop targeted treatments. The goal of this symposium was to provide a forum to introduce the metabolomics field to nutrition researchers. An overview of the state-of-the-art metabolomic technologies used was provided. The impact of some specific nutrients, disease states, or genetic variations and their interaction with the metabolome was discussed by the speakers. Our objectives were as follows: 1) to educate the audience about the use of metabolomics as an innovative tool for linking changes in cell metabolites and genetic variations to nutrient metabolism, energy balance, and the overlying effects on health and disease; 2) to understand the concept of metabolomics and describe the analytical tools and resources available in this area; 3) to introduce the potential application of metabolomics in the field of nutrition research; and 4) to provide specific nutrition-relevant metabolomics study examples in investigating regulation of the metabolic network or metabolic changes resulting from disease states by dietary factors.

Frontiers in Endocrinology, 2013

Advances in Food and Nutrition Research, 2012

Obesity is associated with the metabolic syndrome, a significant risk factor for developing type ... more Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid-mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet-induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health. Adv. Nutr. 2: 304-316, 2011.

Age, 2005

With the goal of discovering genes that contribute to late-onset neurological and ocular disorder... more With the goal of discovering genes that contribute to late-onset neurological and ocular disorders and also genes that extend the healthy life span in mammals, we are phenotyping mice carrying new mutations induced by the chemical N-ethyl-N-nitrosourea (ENU). The phenotyping plan includes basic behavioral, neurohistological, and vision testing in sibling cohorts of mice aged to 18 months, and then evaluation for markers of growth trajectory and stress response in these same cohorts aged up to 28 months. Statistical outliers are identified by comparison to test results of similar aged cohorts, and potential mutants are recovered for re-aging to confirm heritability of the phenotype.

Journal of Nutrition, 2011

Increased adipose tissue positively correlates with circulating inflammatory cytokines such as IL... more Increased adipose tissue positively correlates with circulating inflammatory cytokines such as IL-6. We previously reported that adipose stem cells from genetically obese ob/ob mice produce significantly higher levels of IL-6 compared with other cell types such as adipocytes and macrophages within adipose tissue. We also demonstrated that (n-3) PUFA have antiinflammatory effects on adipocyte IL-6 secretion. Based on these findings, we hypothesized that EPA [20:5 (n-3)] and stearidonic acid [SDA, 18:4 (n-3)] would decrease LPS (200 mg/L)-induced IL-6 secretion and IL-6 mRNA content in the adipose stem cells. SDA (100 mmol/L) and EPA (100 mmol/L) significantly reduced LPS-induced IL-6 secretion and decreased IL-6 mRNA expression. To determine the underlying intracellular mechanisms, we tested whether LPS-induced Toll-like-receptor (TLR) 4 and TLR2 expression were modulated by these fatty acids using Western-blot analysis. EPA and SDA suppressed LPS-induced TLR2 but not TLR4 protein expression in the adipose stem cells. Furthermore, SDA and EPA significantly lowered the activation and translocation of NF-kB, a TLR2 downstream signaling target, while protein expression of extracellular signal-regulated kinases-1/2 were unaffected. Collectively, our results suggest that EPA and SDA inhibit LPS-induced IL-6 secretion and IL-6 mRNA expression in the adipose stem cells by decreasing TRL2-mediated signaling pathways.

Journal of Nutrition, 2010

We investigated the effects of eicosapentaenoic acid (EPA) on prevention (P) and reversal (R) of ... more We investigated the effects of eicosapentaenoic acid (EPA) on prevention (P) and reversal (R) of high saturated-fat (HF) diet-induced obesity and glucose-insulin homeostasis. Male C57BL/6J mice were fed low-fat (LF; 10% energy from fat), HF (45% energy from fat), or a HF-EPA-P (45% energy from fat; 36 g/kg EPA) diet for 11 wk. A 4th group was initially fed HF for 6 wk followed by the HF-EPA-R diet for 5 wk. As expected, mice fed the HF diet developed obesity and glucose intolerance. In contrast, mice fed the HF-EPA-P diet maintained normal glucose tolerance despite weight gain compared with the LF group. Whereas the HF group developed hyperglycemia and hyperinsulinemia, both HF-EPA groups (P and R) exhibited normal glycemia and insulinemia. Further, plasma adiponectin concentration was lower in the HF group but was comparable in the LF and HF-EPA groups, suggesting a role of EPA in preventing and improving insulin resistance induced by HF feeding. Further analysis of adipose tissue adipokine levels and proteomic studies in cultured adipocytes indicated that dietary EPA supplementation of HF diets was associated with reduced adipose inflammation and lipogenesis and elevated markers of fatty acid oxidation. In C57BL/6J mice, EPA minimized saturated fat-induced insulin resistance and this is in part mediated by its effects on fatty acid oxidation and inflammation.

Journal of Nutrition, 2011

Systems genetics is a novel approach for identifying the complex genetic architecture of quantita... more Systems genetics is a novel approach for identifying the complex genetic architecture of quantitative traits and geneenvironment interactions via detection of connections from genetic variation through intermediate phenotypes to overlying systems level phenotypes. This symposium, conducted at the Experimental Biology 2010 conference, aimed at educating nutrition researchers about the use of systems genetics as a tool for linking genetic variation to nutrient metabolism and energy balance and their overlying effects on health and disease. Basic concepts of systems genetics and the analytical framework used in these studies were presented. Further, the utility of genetic reference populations for gene-environment interaction studies along with specific studies addressing genetic variation in responsiveness to nutrients were discussed.

Obesity Reviews, 2012

The renin-angiotensin system (RAS) is classically known for its role in regulation of blood press... more The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. Recently, several local RASs in organs such as brain, heart, pancreas and adipose tissue have also been identified. Evidence from clinical trials suggests that in addition to anti-hypertensive effects, pharmacological inhibition of RAS also provides protection against the development of type-2 diabetes. Moreover, animal models with targeted inactivation of RAS genes exhibit improved insulin sensitivity and are protected from high-fat diet-induced obesity and insulin resistance. Because there is evidence for RAS overactivation in obesity, it is possible that RAS is a link between obesity and insulin resistance. This review summarizes the evidence and mechanistic insights on the associations between RAS, obesity and insulin resistance, with special emphasis on the role of adipose tissue RAS in the pathogenesis of metabolic derangements in obesity.

Cell Death & Disease

Metabolic syndrome (MetS) is a complex, emerging epidemic which disrupts the metabolic homeostasi... more Metabolic syndrome (MetS) is a complex, emerging epidemic which disrupts the metabolic homeostasis of several organs, including liver, heart, pancreas, and adipose tissue. While studies have been conducted in these research areas, the pathogenesis and mechanisms of MetS remain debatable. Lines of evidence show that physiological systems, such as the renin–angiotensin system (RAS) and autophagy play vital regulatory roles in MetS. RAS is a pivotal system known for controlling blood pressure and fluid balance, whereas autophagy is involved in the degradation and recycling of cellular components, including proteins. Although RAS is activated in MetS, the interrelationship between RAS and autophagy varies in glucose homeostatic organs and their cross talk is poorly understood. Interestingly, autophagy is attenuated in the liver during MetS, whereas autophagic activity is induced in adipose tissue during MetS, indicating tissue-specific discordant roles. We discuss in vivo and in vitro s...

Advances in Nutrition: An International Review Journal, 2011

Obesity is associated with the metabolic syndrome, a significant risk factor for developing type ... more Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid-mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet-induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health. Adv. Nutr. 2: 304-316, 2011.

Journal of Nutrition, 2014

Background: Obesity is associated with an overexpansion of adipose tissue, along with increases i... more Background: Obesity is associated with an overexpansion of adipose tissue, along with increases in blood pressure, glycemia, inflammation, and thrombosis. Research to develop nutritional interventions to prevent or treat obesity and its associated diseases is greatly needed. Previously, we demonstrated the ability of eicosapentaenoic acid (EPA) to prevent high-fat (HF) diet-induced obesity, insulin resistance, and inflammation in mice.

Advances in Nutrition: An International Review Journal, 2014

Metabolic pathways are tightly regulated in a tissue-specific manner to maintain whole-body homeo... more Metabolic pathways are tightly regulated in a tissue-specific manner to maintain whole-body homeostasis. Nutrients and hormones control these pathways at the level of transcription, translation, and/or post-translation. Genomic and proteomic tools have been predominantly used to understand metabolic regulation, and only a few studies used metabolomics approaches. Metabolomics is a powerful, unbiased approach that allows comprehensive metabolic analysis of physiologic measurements and energy balance. Thus, nutrimetabolomics can expedite our ability to identify metabolic diseases that are influenced by nutrients and to develop targeted diet-based treatments. Presentations at this symposium reviewed current resources and platforms for metabolic profiling along with statistical and bioinformatics tools for data and pathway analyses. Specific applications of metabolomics were illustrated in nutritional and disease conditions, including polycystic ovary syndrome, diabetes, and obesity and in host-gut microbiome interactions. Adv Nutr 2014;5:792-794.

Bouchard/Genetic and Molecular Aspects of Sport Performance, 2010

Regular physical activity is associated with longevity (Landi et al., 2008; Lanza et al., 2008) a... more Regular physical activity is associated with longevity (Landi et al., 2008; Lanza et al., 2008) and a lowered risk for obesity (Healy et al., 2008) and chronic diseases such as cardiovascular disease (Richardson et al., 2004), type 2 diabetes mellitus (Hu et al., 2004; Jeon et al., 2007), and site-specific cancers such as breast and colon cancer (Irwin et al., 2008; Slattery et al., 1997). Although regular physical activity is inversely associated with obesity, several studies have shown that the beneficial effects of physical activity in terms ...

Frontiers in endocrinology, 2013

Over a third of the US population is obese and at high risk for developing type 2 diabetes, insul... more Over a third of the US population is obese and at high risk for developing type 2 diabetes, insulin resistance, and other metabolic disorders. Obesity is considered a chronic lowgrade inflammatory condition that is primarily attributed to expansion and inflammation of adipose tissues. Indeed, adipocytes produce and secrete numerous proinflammatory and anti-inflammatory cytokines known as adipokines. When the balance of these adipokines is shifted toward higher production of proinflammatory factors, local inflammation within adipose tissues and subsequently systemic inflammation occur. These adipokines including leptin, visfatin, resistin, apelin, vaspin, and retinol binding protein-4 can regulate inflammatory responses and contribute to the pathogenesis of diabetes.These effects are mediated by key inflammatory signaling molecules including activated serine kinases such as c-Jun N-terminal kinase and serine kinases inhibitor κB kinase and insulin signaling molecules including insulin receptor substrates, protein kinase B (PKB, also known as Akt), and nuclear factor kappa B. Bariatric surgery can decrease body weight and improve insulin resistance in morbidly obese subjects. However, despite reports suggesting reduced inflammation and weight-independent effects of bariatric surgery on glucose metabolism, mechanisms behind such improvements are not yet well understood. This review article focuses on some of these novel adipokines and discusses their changes after bariatric surgery and their relationship to insulin resistance, fat mass, inflammation, and glucose homeostasis.

Nutrition research (New York, N.Y.), 2013

Inflammation is a major contributor to the development of atherosclerotic plaque, yet the involve... more Inflammation is a major contributor to the development of atherosclerotic plaque, yet the involvement of liver and visceral adipose tissue inflammatory status in atherosclerotic lesion development has yet to be fully elucidated. We hypothesized that an atherogenic diet would increase inflammatory response and lipid accumulation in the liver and gonadal adipose tissue (GAT) and would correlate with systemic inflammation and aortic lesion formation in low-density lipoprotein (LDL) receptor null (LDLr−/−) mice. For 32 weeks, LDLr −/− mice (n = 10/group) were fed either an atherogenic (high saturated fat and cholesterol) or control (low fat and cholesterol) diet. Hepatic and GAT lipid content and expression of inflammatory factors were measured using standard procedures. Compared with the control diet, the atherogenic diet significantly increased hepatic triglyceride and total cholesterol (TC), primarily esterified cholesterol, and GAT triglyceride content. These changes were accompanied by increased expression of acyl-CoA synthetase long-chain family member 5, CD36, ATP-binding cassette, subfamily A, member 1 and scavenger receptor B class 1, and they decreased the expression of cytochrome P450, family 7 and subfamily a, polypeptide 1 in GAT. Aortic TC content was positively associated with hepatic TC, triglyceride, and GAT triglyceride contents as well as plasma interleukin 6 and monocyte chemoattractant protein-1 concentrations. Although when compared with the control diet, the atherogenic diet increased hepatic tumor necrosis factor α production, they were not associated with aortic TC content. These data suggest that the LDLr−/− mice responded to

Stearoyl-CoA Desaturase Genes in Lipid Metabolism, 2013

ABSTRACT Macrophages are key members of the innate immune system. More recently, a preponderance ... more ABSTRACT Macrophages are key members of the innate immune system. More recently, a preponderance of evidence suggest that macrophages play an important role in metabolic homeostasis. They are implicated in the pathogenesis of metabolic disorders such as type-2 diabetes and atherosclerosis. Human macrophages express SCD1, while rodent ones express both SCD1 and SCD2. Only a few studies have investigated the regulation of SCD1 expression in macrophages and reported that nuclear transcription factors regulate its expression. Of these, liver X receptor and retinoid X receptor increase SCD1 expression, while CCAAT-/enhancer-binding protein beta, farnesoid-X-receptor, and peroxisome proliferator-activated receptor gamma suppress it. Similar to its regulation in other tissues, stearoyl-CoA desaturase (SCD) expression in macrophages is repressed by polyunsaturated fatty acids (PUFA), especially omega-3 PUFA, via nuclear receptors. Lipid-laden macrophages, known as macrophage-derived foam cells, characterize the atherosclerotic lesion. Cholesterol efflux from these foam cells, especially via ATP-binding cassette transporter A1 (ABCA1), provides protection against the cholesterol accumulation in foam cells and further progression of the atherosclerotic plaque. Increased expression of SCD destabilizes ABCA1 and reduces cholesterol efflux in macrophages. Omega-3 PUFA can increase cholesterol efflux from foam cells through inhibition of SCD1. However, SCD inhibition in saturated fat-fed animals promotes, rather than suppresses, atherosclerosis in mouse models with hypercholesterolemia. This is attributed to the proinflammatory environment induced by saturated fatty acid-mediated toll-like receptor 4 activation in these models. Fish oil can ameliorate inflammatory responses and the atherosclerotic lesion development caused by SCD1 inhibition. Overall, the exact roles and mechanisms of SCD in modulating macrophage cholesterol efflux and atherosclerosis merit further investigation.

Nutrition and Disease Prevention, 2004

Nutrition and Disease Prevention, 2004

The Journal of nutrition, 2004

Despite its potential importance in obesity and related disorders, little is known about regulati... more Despite its potential importance in obesity and related disorders, little is known about regulation of lipogenesis in human adipose tissue. To investigate this area at the molecular and mechanistic levels, we studied lipogenesis and the regulation of 1 of its core enzymes, fatty acid synthase (FAS), in human adipose tissue in response to hormonal and nutritional manipulation. As a paradigm for lipogenic genes, we cloned the upstream region of the human FAS gene, compared its sequence to that of FAS orthologs from other species, and identified important regulatory elements that lie upstream of the FAS coding region. Lipogenesis, as assessed by glucose incorporation into lipids, was increased by insulin and more so by the combination of insulin and dexamethasone (Dex, a potent glucocorticoid analogue). In parallel, FAS expression, activity, and gene transcription rate were also significantly increased by these treatments. We also showed that linoleic acid, a representative PUFA, attenuated the actions of insulin and Dex on fatty acid and lipid synthesis as well as FAS activity and expression. Using reporter assays, we determined that the regions responsible for hormonal regulation of the FAS gene lie in the proximal portion of the gene's 5'-flanking region, within which we identified an insulin response element similar to the E-box sequence we identified previously in the rat FAS gene. In summary, we demonstrated that lipogenesis occurs in human adipose tissue and can be induced by insulin, further enhanced by glucocorticoids, and suppressed by PUFA in a hormone-dependent manner.

Advances in Nutrition: An International Review Journal, 2013

Nutrients exert potent effects on metabolism through a variety of regulatory mechanisms, resultin... more Nutrients exert potent effects on metabolism through a variety of regulatory mechanisms, resulting in local and systemic changes in metabolite levels. Numerous studies have focused on mechanisms by which nutrients and disease states regulate metabolism at the gene or protein levels using genomic and proteomic approaches, respectively. However, few studies have investigated nutritional regulation of the whole metabolome. Thus, metabolomic approaches have recently emerged to complement the genomics and proteomics research and to help identify biologically meaningful metabolites and metabolic networks that control cellular responses to genetic and environmental factors, including diet, and to identify metabolic diseases that are influenced by genetic and dietary factors. These large-scale studies expedite our ability to develop targeted treatments. The goal of this symposium was to provide a forum to introduce the metabolomics field to nutrition researchers. An overview of the state-of-the-art metabolomic technologies used was provided. The impact of some specific nutrients, disease states, or genetic variations and their interaction with the metabolome was discussed by the speakers. Our objectives were as follows: 1) to educate the audience about the use of metabolomics as an innovative tool for linking changes in cell metabolites and genetic variations to nutrient metabolism, energy balance, and the overlying effects on health and disease; 2) to understand the concept of metabolomics and describe the analytical tools and resources available in this area; 3) to introduce the potential application of metabolomics in the field of nutrition research; and 4) to provide specific nutrition-relevant metabolomics study examples in investigating regulation of the metabolic network or metabolic changes resulting from disease states by dietary factors.

Frontiers in Endocrinology, 2013

Advances in Food and Nutrition Research, 2012

Obesity is associated with the metabolic syndrome, a significant risk factor for developing type ... more Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid-mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet-induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health. Adv. Nutr. 2: 304-316, 2011.

Age, 2005

With the goal of discovering genes that contribute to late-onset neurological and ocular disorder... more With the goal of discovering genes that contribute to late-onset neurological and ocular disorders and also genes that extend the healthy life span in mammals, we are phenotyping mice carrying new mutations induced by the chemical N-ethyl-N-nitrosourea (ENU). The phenotyping plan includes basic behavioral, neurohistological, and vision testing in sibling cohorts of mice aged to 18 months, and then evaluation for markers of growth trajectory and stress response in these same cohorts aged up to 28 months. Statistical outliers are identified by comparison to test results of similar aged cohorts, and potential mutants are recovered for re-aging to confirm heritability of the phenotype.

Journal of Nutrition, 2011

Increased adipose tissue positively correlates with circulating inflammatory cytokines such as IL... more Increased adipose tissue positively correlates with circulating inflammatory cytokines such as IL-6. We previously reported that adipose stem cells from genetically obese ob/ob mice produce significantly higher levels of IL-6 compared with other cell types such as adipocytes and macrophages within adipose tissue. We also demonstrated that (n-3) PUFA have antiinflammatory effects on adipocyte IL-6 secretion. Based on these findings, we hypothesized that EPA [20:5 (n-3)] and stearidonic acid [SDA, 18:4 (n-3)] would decrease LPS (200 mg/L)-induced IL-6 secretion and IL-6 mRNA content in the adipose stem cells. SDA (100 mmol/L) and EPA (100 mmol/L) significantly reduced LPS-induced IL-6 secretion and decreased IL-6 mRNA expression. To determine the underlying intracellular mechanisms, we tested whether LPS-induced Toll-like-receptor (TLR) 4 and TLR2 expression were modulated by these fatty acids using Western-blot analysis. EPA and SDA suppressed LPS-induced TLR2 but not TLR4 protein expression in the adipose stem cells. Furthermore, SDA and EPA significantly lowered the activation and translocation of NF-kB, a TLR2 downstream signaling target, while protein expression of extracellular signal-regulated kinases-1/2 were unaffected. Collectively, our results suggest that EPA and SDA inhibit LPS-induced IL-6 secretion and IL-6 mRNA expression in the adipose stem cells by decreasing TRL2-mediated signaling pathways.

Journal of Nutrition, 2010

We investigated the effects of eicosapentaenoic acid (EPA) on prevention (P) and reversal (R) of ... more We investigated the effects of eicosapentaenoic acid (EPA) on prevention (P) and reversal (R) of high saturated-fat (HF) diet-induced obesity and glucose-insulin homeostasis. Male C57BL/6J mice were fed low-fat (LF; 10% energy from fat), HF (45% energy from fat), or a HF-EPA-P (45% energy from fat; 36 g/kg EPA) diet for 11 wk. A 4th group was initially fed HF for 6 wk followed by the HF-EPA-R diet for 5 wk. As expected, mice fed the HF diet developed obesity and glucose intolerance. In contrast, mice fed the HF-EPA-P diet maintained normal glucose tolerance despite weight gain compared with the LF group. Whereas the HF group developed hyperglycemia and hyperinsulinemia, both HF-EPA groups (P and R) exhibited normal glycemia and insulinemia. Further, plasma adiponectin concentration was lower in the HF group but was comparable in the LF and HF-EPA groups, suggesting a role of EPA in preventing and improving insulin resistance induced by HF feeding. Further analysis of adipose tissue adipokine levels and proteomic studies in cultured adipocytes indicated that dietary EPA supplementation of HF diets was associated with reduced adipose inflammation and lipogenesis and elevated markers of fatty acid oxidation. In C57BL/6J mice, EPA minimized saturated fat-induced insulin resistance and this is in part mediated by its effects on fatty acid oxidation and inflammation.

Journal of Nutrition, 2011

Systems genetics is a novel approach for identifying the complex genetic architecture of quantita... more Systems genetics is a novel approach for identifying the complex genetic architecture of quantitative traits and geneenvironment interactions via detection of connections from genetic variation through intermediate phenotypes to overlying systems level phenotypes. This symposium, conducted at the Experimental Biology 2010 conference, aimed at educating nutrition researchers about the use of systems genetics as a tool for linking genetic variation to nutrient metabolism and energy balance and their overlying effects on health and disease. Basic concepts of systems genetics and the analytical framework used in these studies were presented. Further, the utility of genetic reference populations for gene-environment interaction studies along with specific studies addressing genetic variation in responsiveness to nutrients were discussed.

Obesity Reviews, 2012

The renin-angiotensin system (RAS) is classically known for its role in regulation of blood press... more The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. Recently, several local RASs in organs such as brain, heart, pancreas and adipose tissue have also been identified. Evidence from clinical trials suggests that in addition to anti-hypertensive effects, pharmacological inhibition of RAS also provides protection against the development of type-2 diabetes. Moreover, animal models with targeted inactivation of RAS genes exhibit improved insulin sensitivity and are protected from high-fat diet-induced obesity and insulin resistance. Because there is evidence for RAS overactivation in obesity, it is possible that RAS is a link between obesity and insulin resistance. This review summarizes the evidence and mechanistic insights on the associations between RAS, obesity and insulin resistance, with special emphasis on the role of adipose tissue RAS in the pathogenesis of metabolic derangements in obesity.