acipimox and Body-Weight

Cigarette smoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance (IR) and hyperinsulinemia. However, the mechanisms behind these effects are unclear. Here we show that nicotine, a major constituent of cigarette smoke, selectively activates AMP-activated protein kinase α2 (AMPKα2) in adipocytes, which in turn phosphorylates MAP kinase phosphatase-1 (MKP1) at serine 334, initiating its proteasome-dependent degradation. The nicotine-dependent reduction of MKP1 induces the aberrant activation of both p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, leading to increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307. Phosphorylation of IRS1 leads to its degradation, protein kinase B inhibition, and the loss of insulin-mediated inhibition of lipolysis. Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues. These results establish AMPKα2 as an essential mediator of nicotine-induced whole-body IR in spite of reductions in adiposity.

Topics: Adipocytes; Adiposity; AMP-Activated Protein Kinases; Animals; Body Composition; Body Weight; Dual Specificity Phosphatase 1; Enzyme Activation; HEK293 Cells; Homeostasis; Humans; Hypolipidemic Agents; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotine; Phosphorylation; Pyrazines; Rats; Serine; Smoking

Smoking is a major risk factor for diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. The health risk associated with smoking can be exaggerated by obesity. We hypothesize that nicotine when combined with a high-fat diet (HFD) can also cause ectopic lipid accumulation in skeletal muscle, similar to recently observed hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD and received twice-daily ip injections of nicotine (0.75 mg/kg body weight) or saline for 10 weeks. Transmission electron microscopy of the gastrocnemius muscle revealed substantial intramyocellular lipid accumulation in close association with intramyofibrillar mitochondria along with intramyofibrillar mitochondrial swelling and vacuolization in nicotine-treated mice on an HFD compared with mice on an HFD treated with saline. These abnormalities were reversed by acipimox, an inhibitor of lipolysis. Mechanistically, the detrimental effect of nicotine plus HFD on skeletal muscle was associated with significantly increased oxidative stress, plasma free fatty acid, and muscle triglyceride levels coupled with inactivation of AMP-activated protein kinase and activation of its downstream target, acetyl-coenzyme A-carboxylase. We conclude that 1) greater oxidative stress together with inactivation of AMP-activated protein kinase mediates the effect of nicotine on skeletal muscle abnormalities in diet-induced obesity and 2) adipose tissue lipolysis is an important contributor of muscle steatosis and mitochondrial abnormalities.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Fatty Acids, Nonesterified; Lipolysis; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondria; Muscle Fibers, Skeletal; Muscle, Skeletal; Nicotine; Obesity; Oxidative Stress; Pyrazines; Risk Factors; Smoking; Triglycerides

To study whether free fatty acids (FFAs) contribute to glucose intolerance in high-fat fed mice, the derivative of nicotinic acid, acipimox, which inhibits lipolysis, was administered intraperitoneally (50 mg kg(-1)) to C57BL/6J mice which had been on a high-fat diet for 3 months. Four hours after administration of acipimox, plasma FFA levels were reduced to 0.46 +/- 0.06 mmol L(-1) compared with 0.88 +/- 0.10 mmol L(-1) in controls (P < 0.001). At this point, the glucose elimination rate after an intravenous glucose load (1 g kg(-1)) was markedly improved. Thus, the elimination constant (KG) for the glucose disposal between 1 and 50 min after the glucose challenge was increased from 0.54 +/- 0.01% min-1 in controls to 0.66 +/- 0.01% min-1 by acipimox (P < 0.001). In contrast, the acute insulin response to glucose (1-5 min) was not significantly different between the groups, although the area under the insulin for the entire 50-min period after glucose administration was significantly reduced by acipimox from 32.1 +/- 2.9 to 23.9 +/- 1.2 nmol L(-1) x 50 min (P = 0.036). This, however, was mainly because of lower insulin levels at 20 and 50 min because of the lowered glucose levels. In contrast, administration of acipimox to mice fed a normal diet did not affect plasma levels of FFA or the glucose elimination or insulin levels after the glucose load. It is concluded that reducing FFA levels by acipimox in glucose intolerant high-fat fed mice improves glucose tolerance mainly by improving insulin sensitivity making the ambient islet function adequate, suggesting that increased FFA levels are of pathophysiological importance in this model of glucose intolerance.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Glucose Tolerance Test; Hypolipidemic Agents; Injections, Intraperitoneal; Insulin; Mice; Mice, Inbred C57BL; Pyrazines

To assess the possible benefits of combined hypolipidemic therapy (acipimox+marine fish oil) on lipid and lipoprotein metabolism, male Wistar rats were fed for 14 days a high sucrose diet (70 cal% sucrose) alone or a high sucrose diet supplemented with acipimox (0.2 g/100 g diet) and/or fish oil (1 ml orally daily; 30 wt% of n-3 PUFA). Feeding a high sucrose diet increased (control: 61 +/- 6 vs HS: 110 +/- 8 nmol.min-1.mg-1, p < 0.001) the activity of acetyl CoA carboxylase in the liver, this was normalized by fish oil but not acipimox alone (HS+FO: 68 +/- 4; HS+ACI: 95 +/- 4; HS+ACI+FO: 71 +/- 2 nmol.min-1.mg-1). Increased triglyceride concentration in serum and muscle tissue (m. soleus and heart) of high sucrose-fed animals was suppressed equally by fish oil, acipimox, and/or both. The cholesterol-lowering effect of fish oil was also present in the liver (p < 0.005). The cholesterol-lowering action of acipimox was accompanied by the accumulation of cholesterol in the liver (p < 0.005), whereas the combination of acipimox+fish oil did not change the liver cholesterol content. After fish oil the LDL binding capacity of liver plasma membranes was increased 1.6-fold (p < 0.001). LDL receptor activity was significantly decreased in HS+ACI group (p < 0.05), but remained unchanged in HS+FO+ACI-fed animals. In summary, (a) the hypotriglyceridemic effect of fish oil in high sucrose-induced HTG is due to its inhibitory effects at the level of fatty acid synthesis; (b) decreased triglyceride production and output from the liver prevent triglyceride accumulation in muscle tissue; (c) the cholesterol-lowering action of acipimox but not fish oil was accompanied by an accumulation of cholesterol in the liver; (d) the latter phenomenon may be due to the opposite effects of both drugs on cholesterol catabolism via hepatic LDL receptors.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Dietary Fats, Unsaturated; Eating; Fatty Acids, Nonesterified; Fish Oils; Insulin; Lipids; Lipolysis; Liver; Male; Pyrazines; Rats; Rats, Wistar; Receptors, LDL; Sucrose; Triglycerides