sr-59230a and Body-Weight

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

Pharmacological β

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Body Weight; Cell Line; Central Nervous System; Diet, High-Fat; Dioxoles; Energy Metabolism; Feeding Behavior; Gene Expression Profiling; Hypothalamus; Immunohistochemistry; Insulin; Insulin Secretion; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Neurons; Propanolamines; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-3; Transcription Factors; Uncoupling Protein 1

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

The hypothalamic AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway is known to play an important role in the control of food intake and energy expenditure. Here, we hypothesize that citrate, an intermediate metabolite, activates hypothalamic ACC and is involved in the control of energy mobilization. Initially, we showed that ICV citrate injection decreased food intake and diminished weight gain significantly when compared to control and pair-fed group results. In addition, we showed that intracerebroventricular (ICV) injection of citrate diminished (80% of control) the phosphorylation of ACC, an important AMPK substrate. Furthermore, citrate treatment inhibited (75% of control) hypothalamic AMPK phosphorylation during fasting. In addition to its central effect, ICV citrate injection led to low blood glucose levels during glucose tolerance test (GTT) and high glucose uptake during hyperglycemic-euglycemic clamp. Accordingly, liver glycogen content was higher in animals given citrate (ICV) than in the control group (23.3+/-2.5 vs. 2.7+/-0.5 microg mL(-1) mg(-1), respectively). Interestingly, liver AMPK phosphorylation was reduced (80%) by the citrate treatment. The pharmacological blockade of beta3-adrenergic receptor (SR 59230A) blocked the effect of ICV citrate and citrate plus insulin on liver AMPK phosphorylation. Consistently with these results, rats treated with citrate (ICV) presented improved insulin signal transduction in liver, skeletal muscle, and epididymal fat pad. Similar results were obtained by hypothalamic administration of ARA-A, a competitive inhibitor of AMPK. Our results suggest that the citrate produced by mitochondria may modulate ACC phosphorylation in the hypothalamus, controlling food intake and coordinating a multiorgan network that controls glucose homeostasis and energy uptake through the adrenergic system.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Body Weight; Citric Acid; Corticosterone; Feeding Behavior; Glucose; Glucose Tolerance Test; Glycogen; Homeostasis; Hypothalamus; Injections, Intraventricular; Insulin; Liver; Male; Multienzyme Complexes; Phosphorylation; Propanolamines; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Satiety Response; Signal Transduction