Nutritional excess is a major forerunner of type 2 diabetes. It enhances the secretion of insulin, but attenuates insulin's metabolic actions in the liver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes, pointing to a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance. Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity seems to be largely elicited downstream of these steps. New findings also connect insulin resistance to extensive metabolic cross-talk between the liver, adipose tissue, pancreas and skeletal muscle. These and other advances over the past 5 years offer exciting opportunities and daunting challenges for the development of new therapeutic strategies for the treatment of type 2 diabetes.

/pdf/insulin-action-and-resistance-in-obesity-and-type-2-diabetes-wz1yvgzkyu.pdf

Insulin action and resistance in obesity and type 2 diabetes

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(15)00090-5.pdf

Adipokines in health and disease

Obesity is frequently associated with chronic inflammation, metabolic and vascular alterations which predispose to the development of the Metabolic Syndrome (MetS). However, the individual obesity-related risk for the MetS is not determined by increased fat mass alone. Heterogeneity of body composition, fat distribution and adipose tissue (AT) function may underly the variable risk to develop metabolic and cardiovascular diseases associated with increased body fat mass. Importantly, an inability to increase AT mass by adipocyte hyperplasia may lead to adipocyte hypertrophy and could induce dysfunction of adipose tissue characterized by decreased insulin sensitivity, hypoxia, increased parameters of intracellular stress, increased autophagy and apoptosis and tissue inflammation. As a result, adipocytes and other AT cells release signals (e.g. adipokines, cells, metabolites) resulting in a proinflammatory, diabetogenic and atherogenic serum profile. These adverse signals may contribute to further AT inflammation and secondary organ damage in target tissues such as liver, brain, endothelium, vasculature, endocrine organs and skeletal muscle. Recently, a specific adipocyte volume threshold has been shown to predict the risk for obesity-associated type 2 diabetes. Most likely, impaired adipocyte function is caused by genetic, behavioural and environmental factors which are not entirely understood. Elucidating the mechanisms of adipocyte dysfunction may lead to the identification of novel treatment targets for obesity and the MetS.

Adipocyte dysfunction, inflammation and metabolic syndrome

In addition to their role in glucose and lipid metabolism, adipocytes respond differentially to physiological cues or metabolic stress by releasing endocrine factors that regulate diverse processes, such as energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation and tissue repair. Both energy-storing white adipocytes and thermogenic brown and beige adipocytes secrete hormones, which can be peptides (adipokines), lipids (lipokines) and exosomal microRNAs. Some of these factors have defined targets; for example, adiponectin and leptin signal through their respective receptors that are expressed in multiple organs. For other adipocyte hormones, receptors are more promiscuous or remain to be identified. Furthermore, many of these hormones are also produced by other organs and tissues, which makes defining the endocrine contribution of adipose tissues a challenge. In this Review, we discuss the functional role of adipose tissue-derived endocrine hormones for metabolic adaptations to the environment and we highlight how these factors contribute to the development of cardiometabolic diseases. We also cover how this knowledge can be translated into human therapies. In addition, we discuss recent findings that emphasize the endocrine role of white versus thermogenic adipocytes in conditions of health and disease. Adipocytes respond to environmental cues, such as metabolic stress, by releasing endocrine factors that modulate diverse physiological processes. This Review discusses the metabolic functions of adipose tissue-derived endocrine hormones and highlights how these factors might contribute to cardiometabolic diseases.

The endocrine function of adipose tissues in health and cardiometabolic disease

The complement system is an essential element of the innate immune response that becomes activated upon recognition of molecular patterns associated with microorganisms, abnormal host cells, and modified molecules in the extracellular environment. The resulting proteolytic cascade tags the complement activator for elimination and elicits a pro-inflammatory response leading to recruitment and activation of immune cells from both the innate and adaptive branches of the immune system. Through these activities, complement functions in the first line of defense against pathogens but also contributes significantly to the maintenance of homeostasis and prevention of autoimmunity. Activation of complement and the subsequent biological responses occur primarily in the extracellular environment. However, recent studies have demonstrated autocrine signaling by complement activation in intracellular vesicles, while the presence of a cytoplasmic receptor serves to detect complement-opsonized intracellular pathogens. Furthermore, breakthroughs in both functional and structural studies now make it possible to describe many of the intricate molecular mechanisms underlying complement activation and the subsequent downstream events, as well as its cross talk with, for example, signaling pathways, the coagulation system, and adaptive immunity. We present an integrated and updated view of complement based on structural and functional data and describe the new roles attributed to complement. Finally, we discuss how the structural and mechanistic understanding of the complement system rationalizes the genetic defects conferring uncontrolled activation or other undesirable effects of complement.

/pdf/complement-activation-regulation-and-molecular-basis-for-2wxuegieio.pdf

Complement activation, regulation, and molecular basis for complement‐related diseases

https://www.cell.com/cell/pdf/S0092-8674(14)00726-0.pdf

Molly E. Kelly

Papers

Adipsin is an Adipokine that Improves β Cell Function in Diabetes