Dual Role of Caspase 8 in Adipocyte Apoptosis and Metabolic Inflammation.

Unlabelled: Caspases are cysteine-aspartic proteases that were initially discovered to play a role in apoptosis. However, caspase 8, in particular, also has additional nonapoptotic roles, such as in inflammation. Adipocyte cell death and inflammation are hypothesized to be initiating pathogenic factors in type 2 diabetes.

Colony stimulating factor-1 producing endothelial cells and mesenchymal stromal cells maintain monocytes within a perivascular bone marrow niche.

Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1) causes severe musculoskeletal defects that may indirectly affect hematopoiesis. Indeed, we show here that osteolineage-derived Csf1 prevented developmental abnormalities but had no effect on monopoiesis in adulthood.

JAK2-IGF1 axis in osteoclasts regulates postnatal growth in mice.

Osteoclasts are specialized cells of the hematopoietic lineage that are responsible for bone resorption and play a critical role in musculoskeletal disease. JAK2 is a key mediator of cytokine and growth factor signaling; however, its role in osteoclasts in vivo has yet to be investigated. To elucidate the role of JAK2 in osteoclasts, we generated an osteoclast-specific JAK2-KO (Oc-JAK2-KO) mouse using the Cre/Lox-P system.

Hepatic Igf1-Deficiency Protects Against Atherosclerosis in Female Mice.

Atherosclerosis is the leading cause of cardiovascular disease (CVD), with distinct sex-specific pathogenic mechanisms that are poorly understood. Aging, a major independent risk factor for atherosclerosis, correlates with a decline in circulating insulin-like growth factor-1 (IGF-1). However, the precise effects of Igf1 on atherosclerosis remain unclear.

Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages.

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive.

Discoidin domain receptor 1-deletion ameliorates fibrosis and promotes adipose tissue beiging, brown fat activity, and increased metabolic rate in a mouse model of cardiometabolic disease.

Objective: Discoidin domain receptor 1 (DDR1) is a collagen binding receptor tyrosine kinase implicated in atherosclerosis, fibrosis, and cancer. Our previous research showed that DDR1 could regulate smooth muscle cell trans-differentiation, fibrosis and calcification in the vascular system in cardiometabolic disease. This spectrum of activity led us to question whether DDR1 might also regulate adipose tissue fibrosis and remodeling.

Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation.

During obesity, macrophages can infiltrate metabolic tissues, and contribute to chronic low-grade inflammation, and mediate insulin resistance and diabetes. Recent studies have elucidated the metabolic role of JAK2, a key mediator downstream of various cytokines and growth factors. Our study addresses the essential role of macrophage JAK2 in the pathogenesis to obesity-associated inflammation and insulin resistance.

Hepatic JAK2 protects against atherosclerosis through circulating IGF-1.

Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown.

Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome.

Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood.

FAK signalling controls insulin sensitivity through regulation of adipocyte survival.

Focal adhesion kinase (FAK) plays a central role in integrin signalling, which regulates growth and survival of tumours. Here we show that FAK protein levels are increased in adipose tissue of insulin-resistant obese mice and humans. Disruption of adipocyte FAK in mice or in 3T3 L1 cells decreases adipocyte survival.

Janus Kinase 2 (JAK2) Dissociates Hepatosteatosis from Hepatocellular Carcinoma in Mice.

Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosis promotes liver cancer, and the molecular mechanisms that control the progression in this disease spectrum remain largely elusive.

Methods for Assessing the In Vivo Role of PTEN in Glucose Homeostasis.

PTEN plays an important role in diabetes pathogenesis not only as a key negative regulator of the PI3K/Akt pathway required for insulin action, but also via its role in other cell processes required to maintain metabolic homeostasis. We describe the generation of tissue-specific PTEN knockout mice and models of both type 1 and type 2 diabetes, which we have found useful for the study of diabetes pathogenesis. We also outline common methods suitable for the characterization of glucose homeostasis in rodent models, including techniques to measure beta cell function and insulin sensitivity.

JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice.

Aims/hypothesis: Non-shivering thermogenesis in adipose tissue can be activated by excessive energy intake or following cold exposure. The molecular mechanisms regulating this activation have not been fully elucidated. The Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway mediates the signal transduction of numerous hormones and growth factors that regulate adipose tissue development and function, and may play a role in adaptive thermogenesis.

DJ-1 links muscle ROS production with metabolic reprogramming and systemic energy homeostasis in mice.

Reactive oxygen species (ROS) have been linked to a wide variety of pathologies, including obesity and diabetes, but ROS also act as endogenous signalling molecules, regulating numerous biological processes. DJ-1 is one of the most evolutionarily conserved proteins across species, and mutations in DJ-1 have been linked to some cases of Parkinson's disease. Here we show that DJ-1 maintains cellular metabolic homeostasis via modulating ROS levels in murine skeletal muscles, revealing a role of DJ-1 in maintaining efficient fuel utilization.

Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis.

Both type 1 and type 2 diabetes are associated with insufficient functional β-cell mass. Understanding intracellular signaling pathways associated with this decline is important in broadening our understanding of the disease and potential therapeutic strategies. The hypoxia inducible factor pathway (HIF) plays a critical role in cellular adaptation to hypoxic conditions.

SIRT1 activation ameliorates hyperglycaemia by inducing a torpor-like state in an obese mouse model of type 2 diabetes.

Aims/hypothesis: Nutrient overabundance and diminished physical activity underlie the epidemic of obesity and its consequences of insulin resistance and type 2 diabetes. These same phenomena, obesity and insulin resistance, are also observed in mammals as they ready themselves for the nutrient deprivation of winter, yet their plasma glucose does not rise. Given the role of silent information regulator 2 (Sir2) and its mammalian orthologue, Sirt1, in survival and life extension during energy deprivation, we hypothesised that enhancing its activity may reduce the insensible energy loss engendered by hyperglycaemia and glycosuria.

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action.

Aims/hypothesis: Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagon-like peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action.

Methods: We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines.

PTEN deletion in pancreatic α-cells protects against high-fat diet-induced hyperglucagonemia and insulin resistance.

An aberrant increase in circulating catabolic hormone glucagon contributes to type 2 diabetes pathogenesis. However, mechanisms regulating glucagon secretion and α-cell mass are not well understood. In this study, we aimed to demonstrate that phosphatidylinositol 3-kinase (PI3K) signaling is an important regulator of α-cell function.

Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions.

Aims/hypothesis: Diabetes mellitus represents a significant burden on the health of the global population. Both type 1 and type 2 diabetes share a common feature of a reduction in functional beta cell mass. A newly discovered ubiquitination molecule HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as MULE or ARF-BP1]) is a critical regulator of p53-dependent apoptosis.

Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex.

Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis.

Adipocyte-specific deficiency of Janus kinase (JAK) 2 in mice impairs lipolysis and increases body weight, and leads to insulin resistance with ageing.

Aims/hypothesis: The growing obesity epidemic necessitates a better understanding of adipocyte biology and its role in metabolism. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway mediates signalling by numerous cytokines and hormones that regulate adipocyte function, illustrating the physiological importance of adipose JAK-STAT. The aim of this study was to investigate potential roles of adipocyte JAK2, an essential player in the JAK-STAT pathway, in adipocyte biology and metabolism.

Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate.

Pancreatic endocrine cells expand rapidly during embryogenesis by neogenesis and proliferation, but during adulthood, islet cells have a very slow turnover. Disruption of murine retinoblastoma tumor suppressor protein (Rb) in mature pancreatic β-cells has a limited effect on cell proliferation. Here we show that deletion of Rb during embryogenesis in islet progenitors leads to an increase in the neurogenin 3-expressing precursor cell population, which persists in the postnatal period and is associated with increased β-cell mass in adults.

In vivo knockdown of adipocyte erythropoietin receptor does not alter glucose or energy homeostasis.

The growing prevalence of obesity and diabetes necessitate a better understanding of the role of adipocyte biology in metabolism. Increasingly, erythropoietin (EPO) has been shown to have extraerythropoietic and cytoprotective roles. Exogenous administration has recently been shown to have beneficial effects on obesity and diabetes in mouse models and EPO can modulate adipogenesis and insulin signaling in 3T3-L1 adipocytes.

Dual role of VAMP8 in regulating insulin exocytosis and islet β cell growth.

Optimal insulin secretion required to maintain glucose homeostasis is the summation of total pancreatic islet β cell mass and intrinsic secretory capacity of individual β cells, which are regulated by distinct mechanisms that could be amplified by glucagon-like-peptide-1 (GLP-1). Because of these actions of GLP-1 on islet β cells, GLP-1 has been deployed to treat diabetes. We employed SNARE protein VAMP8-null mice to demonstrate that VAMP8 mediates insulin granule recruitment to the plasma membrane, which partly accounts for GLP-1 potentiation of glucose-stimulated insulin secretion.