Metabolism, Obesity, and Diabetes Mellitus

Abstract

O besity and diabetes mellitus remain the leading causes of reduced health span and life span throughout the world. Hence, it is not surprising that these areas are at the center of highly active areas of research. The identification of novel mechanisms underlying these metabolic disorders sets the stage for uncovering new potential therapeutic strategies. In this issue of highlights in Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB), we review recently published papers in the journal that add to our understanding of causes and consequences of obesity and diabetes mellitus and how these disorders impact metabolic function. Collectively, these studies in cultured cells to in vivo animal models to human subjects add to the growing body of evidence that both cell-intrinsic and cell-cell communication mechanisms collaborate in metabolic disorders to cause obesity, insulin resistance, and diabetes mellitus and its complications. Highlights Diabetes mellitus poses a major risk to health and longevity. Spurred, at least in part, by the rise in obesity, diabetes mel-litus has become the seventh leading cause of death in the United States 1-3 and a major risk factor for the development of cardiovascular disease and its complications. 4-6 The intimate relationships that entwine obesity, insulin resistance, and diabetes mellitus with the immune system and regulation of metabolism are being increasingly unraveled. The interplay between tissue resident versus infiltrating immune cells in the metabolic organs is complex, and the potential mechanistic influence of immune cell (dys)function and insulin resistance is under intense investigation. 7-11 Furthermore, the identification of protective roles for immune cells, such as macrophages, in countering the derangements affecting insulin resistance is adding new insights to these complex phenomena. 12,13 In addition, the influence of both cell-intrinsic and intercellular communication mechanisms in metabolic organs is being increasingly recognized as central to the organism's response to endogenous and exogenous stresses. Mechanisms, such as direct cell-cell contact and intercellular communication instigated by extracellular vesicles, such as exosomes, are being implicated in the development of metabolic dysfunction. 7,14-17 In this contribution to the highlights series in ATVB, we review recent studies published in the journal in the areas of obesity, diabetes mellitus, and metabolism that add to the body of data identifying mechanisms and consequences of metabolic dys-function. Further, these studies point to new therapeutic avenues and modalities for obesity and diabetes mellitus. From work in cultured cells to animal models of metabolic disorders and to studies in human subjects, recent work published in ATVB is providing new insight toward understanding and tackling these complex disorders. Adipocyte Biology: Effects on Vascular and Inflammatory Homeostasis Adipose tissue is a complex and highly active metabolic organ, and adipose dysfunction is linked to cardiovascular disease. 18 Adipose tissues are diverse, and specific depots have been characterized as good fat versus bad fat. What accounts for these differences? Indeed, beyond adipocytes, multiple classes of immune cells, such as macrophages, T and B lymphocytes, T regulatory cells, and NK (natural killer) cells; nerve tissue, stromovascular cells, and endo-thelial cells (ECs), all housed within a biologically active connective tissue matrix, populate this tissue. 19 Recent studies have identified cell-intrinsic and cell-cell communication pathways linked to obesity and diabetes mel-litus in adipose and other metabolic tissues, such as liver, skeletal muscle, and brain, and how their properties may affect vascular and inflammatory health and homeostasis. For example, cell-intrinsic roles for adipocytes in metabolic dysfunction were illustrated by studies in mice with adipocyte-specific deletion of NOX4 (NADPH [nicotina-mide adenine dinucleotide phosphate] oxidase 4), using the Adipoq cre recombinase strategy for specific deletion of genes of interest in adipocytes. Mice were fed a high-fat/ high-sucrose diet with added cholesterol. Mice devoid of adipocyte NOX4 exhibited no differences in body weight throughout the study but experienced a delay in the onset of insulin resistance with an initial attenuation of adipose tissue inflammation that normalized with the sustained feeding with this pro-obesogenic diet. 20 Early, but not later, in the feeding with this diet, the epididymal white adipose tissue displayed a reduction in 4-hydroxynonenal staining-a marker of oxidative stress-thereby suggesting that NOX4-derived reactive oxygen species may contribute to the development of insulin resistance. Adipose and liver