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Kim, Jason

One or more keywords matched the following properties of Kim, Jason

Property	Value
overview	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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Value

overview

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.

One or more keywords matched the following items that are connected to Kim, Jason

Item Type	Name
Academic Article	Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance.
Academic Article	COMP-angiopoietin-1 enhances skeletal muscle blood flow and insulin sensitivity in mice.
Academic Article	Increased hepatic insulin action in diet-induced obese mice following inhibition of glucosylceramide synthase.
Academic Article	Cytoplasmic polyadenylation element binding protein deficiency stimulates PTEN and Stat3 mRNA translation and induces hepatic insulin resistance.
Academic Article	Gut-derived serotonin is a multifunctional determinant to fasting adaptation.
Academic Article	CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance.
Academic Article	Role of the mixed-lineage protein kinase pathway in the metabolic stress response to obesity.
Academic Article	Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart.
Academic Article	Unraveling the temporal pattern of diet-induced insulin resistance in individual organs and cardiac dysfunction in C57BL/6 mice.
Academic Article	Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity.
Academic Article	Txnip balances metabolic and growth signaling via PTEN disulfide reduction.
Academic Article	Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice.
Academic Article	Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress.
Academic Article	Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle.
Academic Article	Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance.
Academic Article	Deficiency of phosphoinositide 3-kinase enhancer protects mice from diet-induced obesity and insulin resistance.
Academic Article	JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation.
Concept	Diet, Atherogenic
Concept	Diet, Fat-Restricted
Concept	Diet
Academic Article	Diet-induced obesity mediated by the JNK/DIO2 signal transduction pathway.
Academic Article	RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice.
Academic Article	MicroRNA-378 controls classical brown fat expansion to counteract obesity.
Academic Article	The PPAR?-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway.
Academic Article	Deficiency of the tumor promoter gene wip1 induces insulin resistance.
Academic Article	Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance.
Academic Article	Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance.
Academic Article	Genetic ablation of lymphocytes and cytokine signaling in nonobese diabetic mice prevents diet-induced obesity and insulin resistance.
Academic Article	Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice.
Academic Article	Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress.
Academic Article	Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance.
Academic Article	Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance.
Academic Article	Gingerenone A, a polyphenol present in ginger, suppresses obesity and adipose tissue inflammation in high-fat diet-fed mice.
Academic Article	A Protein Scaffold Coordinates SRC-Mediated JNK Activation in Response to Metabolic Stress.
Academic Article	Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders.
Academic Article	Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity.
Academic Article	Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice.
Academic Article	Interleukin-6 derived from cutaneous deficiency of stearoyl-CoA desaturase- 1 may mediate metabolic organ crosstalk among skin, adipose tissue and liver.
Academic Article	Myeloid-specific Acat1 ablation attenuates inflammatory responses in macrophages, improves insulin sensitivity, and suppresses diet-induced obesity.
Academic Article	GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity.
Academic Article	Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice.
Academic Article	Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice.
Academic Article	Muscle-Specific Insulin Receptor Overexpression Protects Mice From Diet-Induced Glucose Intolerance but Leads to Postreceptor Insulin Resistance.
Academic Article	Thioredoxin Interacting Protein Is Required for a Chronic Energy-Rich Diet to Promote Intestinal Fructose Absorption.
Academic Article	Maternal exposure to high-fat diet during pregnancy and lactation predisposes normal weight offspring mice to develop hepatic inflammation and insulin resistance.
Academic Article	Distinct Changes in Gut Microbiota Are Associated with Estradiol-Mediated Protection from Diet-Induced Obesity in Female Mice.
Academic Article	CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease.
Concept	Diet, High-Fat
Academic Article	Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance.
Academic Article	Differential effects of Akkermansia-enriched fecal microbiota transplant on energy balance in female mice on high-fat diet.
Academic Article	IFN?-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease.
Academic Article	Mitochondria-Targeted DNA Repair Glycosylase hOGG1 Protects Against HFD-Induced Liver Oxidative Mitochondrial DNA Damage and Insulin Resistance in OGG1-Deficient Mice.

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