sr-59230a and Obesity

The sympathetic nervous system (SNS) regulates energy homeostasis in part by governing fatty acid liberation from adipose tissue. We first examined whether SNS activity toward discrete adipose depots changes in response to a weight loss diet in mice. We found that SNS activity toward each adipose depot is unique in timing, pattern of activation, and habituation with the most dramatic contrast between visceral and subcutaneous adipose depots. Sympathetic drive toward visceral epididymal adipose is more than doubled early in weight loss and then suppressed later in the diet when weight loss plateaued. Coincident with the decline in SNS activity toward visceral adipose is an increase in activity toward subcutaneous depots indicating a switch in lipolytic sources. In response to calorie restriction, SNS activity toward retroperitoneal and brown adipose depots is unaffected. Finally, pharmacological blockage of sympathetic activity on adipose tissue using the β3-adrenergic receptor antagonist, SR59230a, suppressed loss of visceral adipose mass in response to diet. These findings indicate that SNS activity toward discrete adipose depots is dynamic and potentially hierarchical. This pattern of sympathetic activation is required for energy liberation and loss of adipose tissue in response to calorie-restricted diet.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Adrenergic beta-3 Receptor Antagonists; Animals; Body Weight; Caloric Restriction; Diet, Reducing; Energy Intake; Energy Metabolism; Epididymis; Intra-Abdominal Fat; Lipolysis; Male; Mice, Inbred C57BL; Norepinephrine; Obesity; Peritoneum; Propanolamines; Subcutaneous Fat; Sympathetic Nervous System; Weight Loss

Neutrophil gelatinase-associated lipocalin (NGAL, lipocalin 2 or LCN2) is an iron carrier protein whose circulating level is increased by kidney injury, bacterial infection and obesity, but its metabolic consequence remains elusive. To study physiological role of LCN2 in energy homeostasis, we challenged female Lcn2 knockout (KO) and wild-type (WT) mice with high fat diet (HFD) or cold exposure. Under normal diet, physical constitutions of Lcn2 KO and WT mice were indistinguishable. During HFD treatment, Lcn2 KO mice exhibited larger brown adipose tissues (BAT), consumed more oxygen, ate more food and gained less body weights as compared to WT mice. When exposed to 4 °C, KO mice showed higher body temperature and more intense

Topics: Adipose Tissue, Brown; Adrenergic beta-3 Receptor Antagonists; Animals; Biological Transport; Cold Temperature; Diet, High-Fat; Eating; Energy Metabolism; Enterobactin; Female; Fluorodeoxyglucose F18; Gene Expression Regulation; Lipocalin-2; Mice; Mice, Knockout; Obesity; Oxygen Consumption; Propanolamines; Receptors, Adrenergic, beta-3; RNA, Messenger; Signal Transduction; Thermogenesis

Obesity-associated cardiovascular disease exerts profound human and monetary costs, creating a mounting need for cost-effective and relevant in vivo models of the complex metabolic and vascular interrelationships of obesity. Obesity is associated with endothelial dysfunction and inflammation. Free fatty acids (FFA), generated partly through beta-adrenergic receptor-mediated lipolysis, may impair endothelium-dependent vasodilation (EDV) by proinflammatory mechanisms. beta-Adrenergic antagonists protect against cardiovascular events by mechanisms not fully defined. We hypothesized that beta antagonists may exert beneficial effects, in part, by inhibiting lipolysis and reducing FFA. Further, we sought to evaluate the fat-fed rat as an in vivo model of obesity-induced inflammation and EDV. Control and fat-fed rats were given vehicle or beta antagonist for 28 d. Serum FFA were measured to determine the association to serum IL6, TNFalpha, and C-reactive protein and to femoral artery EDV. Compared with controls, fat-fed rats weighed more and had higher FFA, triglyceride, leptin, and insulin levels. Unexpectedly, in control and fat-fed rats, beta antagonism increased FFA, yet inflammatory cytokines were reduced and EDV was preserved. Therefore, reduction of FFA is unlikely to be the mechanism by which beta antagonists protect the endothelium. These results reflect the need for validation of ex vivo models of obesity-induced inflammation and endothelial dysfunction, concurrent with careful control of dietary fat composition and treatment duration.

Topics: Acetylcholine; Adrenergic beta-Antagonists; Animals; Blood Flow Velocity; Body Weight; Cytokines; Dietary Fats; Disease Models, Animal; Endothelium, Vascular; Inflammation; Male; Obesity; Propanolamines; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Vasodilation