Lab Focus
Central Integrative Signals
Leptin and insulin from the circulation interact with specific insulin and leptin receptors in the arcuate nucleus of the hypothalamus (ARC). When peripheral insulin and leptin are high, they act through ARC insulin and leptin receptors to release α-melanocyte stimulating hormone (MSH) which activates neurons in the paraventricular nucleus (PVN) to cause a net catabolic response; i.e., reduce food intake, increased energy expenditure and loss of body weight.
When peripheral insulin and leptin are low, the ARC neurons do not get insulin or leptin activation. This increases AgRP release in the ARC nucleus which causes a net anabolic response to increase food intake, decrease energy expenditure and promote body weight gain. Interruption of this central homeostatic loop can result in obesity and insulin resistance.
The Metabolic Syndrome
The epidemic of obesity stems from a clash between genes that allowed our ancestors to survive extended periods of famine and the caloric excess and sedentary lifestyle of the modern world. Obesity is a major risk factor for the metabolic syndrome, a constellation of metabolic impairments that includes insulin resistance, diabetes and heart disease. The increased incidence of obesity makes it imperative to understand the regulation of food intake and body weight.
Hormonal signals whose secretion is proportional to body fat (adiposity signals, leptin and insulin) reduce food intake and body weight by directly stimulating receptors in the ARC. In addition, sex hormones influence the efficacy of adiposity hormones as they interact with food intake control systems in the brain. The levels of insulin and leptin in the blood are correlated with body fat, insulin being related mainly to visceral fat and leptin to subcutaneous fat. Since females carry more fat subcutaneously and males carry more fat viscerally, leptin correlates better with total body fat in females and insulin correlates better in males.
Symptoms of the metabolic syndrome, including increased visceral adipose tissue, insulin resistance and increased visceral obesity, begin appearing in many women experiencing menopause and developing estrogen deficiency. Even in women who do not gain weight after menopause, fat shifts from a subcutaneous location into the abdomen. One goal of the lab is to establish animal models of these processes, using aging female rats to dissect specific mechanisms involved in postmenopausal weight gain, fat depot shifts and the cellular mechanisms of central insulin and leptin sensitivity.
