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Metabolic and Molecular Research in Obesity, Type 2 Diabetes, and Diabetic Heart Disease

My research for almost 30 years has focused on obesity, insulin resistance, and type 2 diabetes, and I have made a significant contribution to the field with 166 peer-reviewed publications, mostly in high-impact scientific journals, such as Nature, Science, and Cell Metabolism. Insulin resistance is a major cause of type 2 diabetes, and my research program has largely explored the molecular link between inflammation and insulin resistance using transgenic mice with elegant in vivo metabolic experiments and molecular approaches. Heart disease is a leading cause of death for people with diabetes, and my research also investigates the role of inflammation and altered myocardial metabolism in diabetic cardiomyopathy. As a leading expert on mouse metabolism and diabetes research and as Program Director of NIH-funded National Mouse Metabolic Phenotyping Center at UMass (https://www.mmpc.org/), my group has also studied more than 400 genetic mouse models of human diseases and collaborated with academic and industry investigators worldwide in joint efforts to understand the etiology of type 2 diabetes and its complications and to identify potential therapeutic targets. Overall, my research projects are highly translational in their abilities to better understand the etiology and pathogenesis of type 2 diabetes and its complications in humans.

Project 1: Role of GRP78 and Unfolded Protein Response in Macrophage Function and Insulin Resistance in Diet-Induced Obesity

We have recently found that obesity-mediated inflammation is associated with M1 polarization of macrophages and increased secretion of inflammatory cytokines and their deleterious effects on skeletal muscle insulin signaling and glucose metabolism. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone, and our recently published work showed that GRP78 modulates unfolded protein response (UPR) and ER homeostasis. Based on these findings, we have recently generated mice with conditional deletion of Grp78 in myeloid cells (Lyz-Grp78-/-), and Lyz-Grp78-/- mice are shown to be protected from obesity-mediated insulin resistance, and the underlying mechanism involves upregulation of ATF-4 and other UPR elements with increased alternatively-activated (M2) macrophages, resulting in increased insulin signaling and glucose metabolism in skeletal muscle. Our findings implicate a potential role of ER stress and UPR in macrophage function, and we are continuing to investigate the effects of obesity in macrophages and other immune cells.

Project 2: Role of IFNg and IL-1a in Obesity-Mediated Inflammation and Insulin Resistance

Interferon-g (IFNg) and IL-1a are major inflammatory cytokines elevated in obesity, but their role in obesity-mediated insulin resistance and type 2 diabetes is unknown. As a primary modulator of the macrophage phenotype, IFNg promotes a strong pro-inflammatory M1 macrophage response that correlates with macrophage recruitment to metabolic organs in obesity. We have recently generated mice with conditional deletion of IFNg receptor (Lyz-IFNgR2 KO) to disrupt the IFNg signaling in myeloid cells, and we are currently investigating the effects of diet-induced obesity in Lyz-IFNgR2 KO mice. We have also generated mice with conditional deletion of IL-1a in myeloid cells (Lyz-IL1a KO) to determine the effects of myeloid cells lacking IL-1a in obesity-mediated inflammation and insulin resistance.

Project 3: Role of Altered Gut Microbiome in Obesity and Type 2 Diabetes

The gut microbiota and their secreted metabolites have profound effects on host energy balance and metabolism. Although recent studies have shown altered gut microbial communities in obese and diabetic humans and animals, their role in the pathogenesis of metabolic diseases remains unclear. We have recently found that antibiotic-mediated alteration in gut microbiota affects energy balance and obesity during chronic high-fat feeding, and these effects are differentially regulated in male and female mice. Using antibiotics, fecal microbiota transplant, and ovariectomy, we are investigating the underlying mechanism of gender-selective effects of altered gut microbiota on energy homeostasis and metabolism.

Project 4: Role of ER Stress and Inflammation in Myocardial Metabolism and Diabetic Heart Disease

We were the first to demonstrate that diet-induced obesity causes myocardial inflammation and affects key metabolic signaling processes, suggesting a possible role of inflammation in diabetic heart disease. We have also found that diet-induced obesity causes insulin resistance in the heart with defects in myocardial insulin signaling and glucose metabolism. Based on these findings, we have recently generated mice with heart-selective deletion of the c-Jun kinase (JNK), GRP78, and uncoupling protein (UCP) to determine the role of excess lipid oxidation and ER stress in myocardial inflammation and insulin resistance in obesity. Using these cardiac mouse models and in vivo imaging system to assess cardiac function and structure, we are continuing to identify new molecular pathways by which obesity affects myocardial metabolism and causes diabetic heart disease.

Project 5: Role of Anti-Inflammatory Cytokine, IL-10 in Regulation of Glucose Metabolism, Insulin Signaling, and Skeletal Muscle Myogenesis

We have initially made two important discoveries: 1) In diet-induced obesity, inflammation develops in skeletal muscle with macrophage infiltration and locally elevated inflammatory cytokines, and 2) cytokines regulate glucose metabolism and insulin signaling in skeletal muscle. Based on these findings, we have generated transgenic mice with muscle-selective overexpression of IL-10 (MIL-10), and MIL-10 mice are protected from obesity-mediated inflammation and insulin resistance in skeletal muscle. We have also found that MIL-10 mice remain more insulin sensitive with increased glucose metabolism in aging, suggesting a potential role of muscle inflammation in aging-associated insulin resistance. Interestingly, we have found increased muscle mass in MIL-10 mice, and we are continuing to investigate the molecular mechanisms by which IL-10 regulates muscle inflammation, insulin signaling, and myogenesis and identify potential therapeutic targets for the treatment of insulin resistance (pre-diabetes) in obesity and aging.

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