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Body Weight Regulation, Obesity and Type 2 Diabetes

Obesity is a major risk factor for the metabolic syndrome, diabetes mellitus and cardiovascular disease.  Rather than reflecting passive accumulation of excess body fat, most forms of obesity arise from an upward re-setting of the defended level of body weight. Body weight regulation is a complex process that involves negative feedback from humoral “adiposity signals” that circulate in the blood in proportion to body fat content and act within the central nervous system (CNS) to promote negative energy balance (i.e., energy intake less than expenditure).  Because calorically restricted diets and other interventions causing weight loss lower plasma levels of adiposity signals, they trigger responses that favor positive energy balance and recovery of lost weight.  Thus, deviation from the regulated level of body fat content elicits compensatory responses that promote stability of body fat stores over time – this is how energy homeostasis works.

The adipocyte hormone leptin is a prototypical adiposity negative feedback signal to brain systems controlling energy balance and has emerged as a critical hormone for energy homeostasis.  Ongoing work led by Dr. Michael Schwartz and Dr. Gregory Morton focus on key regions in the CNS where leptin regulates energy balance and the intracellular and trans-synaptic neuronal pathways whereby leptin decreases food intake and increases energy expenditure in rodent models.

Brain Systems Controlling Energy Balance
Arcuate NucleusThe hypothalamic Arcuate Nucleus after histochemical detection of messenger RNA using a method known as fluorescent in situ hybridization. Left panel: Neurons that express the gene encoding NPY (green) or Agrp (red) are shown. Cells in which both NPY and Agrp mRNA is present both show up as yellow-orange, due to merging of the green and red staining of the two mRNA species.  The blue DAPI counterstain detects cell nuclei. Right panel:  Neurons that express the gene encoding NPY (green) or POMC (red) are shown.  Note that unlike co-expression of NPY and Agrp genes (left), NPY and POMC genes are not co-expressed by the same cells (right).  Images courtesy of the laboratory of Michael Schwartz, MD.×

The existence of a homeostatic system that promotes stability of body fat stores seems at odds with the ease with which many individuals gain weight.  Some have argued that energy homeostasis operates primarily to defend against weight loss, and that biological defense against weight gain either does not exist or is comparatively much less robust.  According to this view, obesity is seen as the natural result of living in an ‘obesigenic’ environment.  An alternative hypothesis proposes that although the energy homeostasis system defends against weight gain as well as weight loss under normal circumstances, genetic or acquired defects (or interactions between them) that impair the function of this system lie at the heart of obesity pathogenesis.  The latter view reconciles compelling evidence that a substantial percentage of our population is inherently protected against weight gain, and justifies efforts to better understand leptin resistance and other regulatory defects that predispose to obesity.  The Schwartz and Morton labs are actively investigating this key area.

Leptin and Insulin Regulation in Peripheral Tissues

In addition to its role in energy homeostasis, leptin also plays a role to regulate insulin sensitivity in peripheral tissues.  Interestingly, this effect is mediated through CNS pathways that are closely related to those involved in its effects on energy balance, and the mechanisms that underlie this effect are an ongoing research focus led by Dr. Morton’s group. One implication of this work is that if leptin and other humoral signals play a physiological role to regulate both energy balance and insulin sensitivity, resistance to these inputs may favor both weight gain and insulin resistance as primary events.  As this process evolves, insulin resistance and metabolic dysfunction worsens as a consequence of the resultant obesity.

In addition, leptin is a cytokine required for intact immune function.  Work led by Dr. Brent Wisse has focused on the ability of leptin and other peripheral inputs to trigger inflammation within the hypothalamus. In many conditions associated with acute inflammation, plasma leptin levels are increased and leptin has both direct and indirect effects on macrophage function that favor classical activation. In pathological conditions pro-inflammatory cytokines such as TNF, IL1 and IL-6 share in common the ability to cause the complex behavioral and autonomic features of the ‘sickness response’ common to many acute illnesses, including reduced food intake, water intake and locomotor activity, along with fever, and activation of the hypothalamic-pituitary-adrenal axis.  Ongoing work in Dr. Wisse’s laboratory suggests that activation of inflammatory signals within one or more CNS cell types is essential to the pathogenesis of inflammatory anorexia, whereas circulating cytokines are not. Identifying the role of inflammation in neurons, microglia and CNS endothelial cells in causing the ‘sickness’ response is a goal of current work.

Unraveling these complex interactions requires a multidisciplinary approach that lies at the heart of research conducted by the Diabetes and Obesity Center of Excellence.

Weight Loss and Adipose Tissue Inflammation

Macrophages (an immune cell) are recruited to adipose tissue (fat) in states of obesity and insulin resistance, and are believed to contribute to inflammation, insulin resistance and complications, such as cardiovascular disease. In ongoing studies, Dr. Renee LeBoeuf investigates the consequences of weight loss on adipose tissue inflammation. Her studies have demonstrated that weight loss results in accumulation of macrophages in adipose tissue. These adipose tissue macrophages may modulate adipocyte metabolism and take up lipids released during adipocyte lipolysis and cell death during weight loss. Thus, adipose tissue macrophages play important roles both during weight gain and weight loss. These studies are closely related to the area of Lipid Metabolism and Inflammation.