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Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18[sup.-/-] mice resulted from accumulation of fat tissue based on increased food intake. Il18[sup.-/-] mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18[sup.-/-] mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18[sup.-/-] mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18[sup.-/-] mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity., Author(s): Mihai G Netea (corresponding author) [1, 2, 8]; Leo A B Joosten [3, 8]; Eli Lewis [2]; Dalan R Jensen [4]; Peter J Voshol [5]; Bart Jan Kullberg [1]; [...]

The role of isoproterenol in the regulation of lipoprotein lipase (LPL) activity in adipose tissue and skeletal muscle was investigated in 25 normal healthy volunteers. Subjects were randomized to three infusion groups, one was saline and the other two consisted to different concentration of isoproterenol. Isoproterenol induced increases in plasma insulin levels, plasma glucose, free fatty acids, and glycerol but not muscle or adipose tissue LPL. It was suggested that isoproterenol may be involved in the regulation of LPL in muscle or adipose tissue.

Mice which were bred to produce abnormally high amounts of the glucose transporter GLUT-4 in their adipose tissue become obese because more glucose is used in making fatty acids than consumed as an energy source in muscles. These mice also exhibited an increase in the activity of lipoprotein lipase (LPL) in their adipose tissue, while LPL activity was less in their muscle tissues. These observations imply that the partitioning of glucose for energy use and fat deposition is altered in obesity.

To examine the relative impact of diet and meal composition on lipoprotein lipase (LPL), high fat (60% of energy) (HF) and high carbohydrate (68%) (HC) diets were fed to Sprague-Dawley rats for 2-3 wk, followed by overnight food deprivation and a meal of the same composition. Heparin-releasable LPL activities, mass and mRNA were measured in heart, diaphragm and soleus muscle and epididymal fat after food deprivation and 1, 2, 4 and 8 h postprandially. No effect of dietary macronutrient composition on LPL activity, protein or mRNA in food-deprived rats was demonstrated. However, in cardiac and diaphragm muscle, heparin-releasable LPL activity was suppressed by HC but stimulated by HF meal-feeding at 4 h. Moreover, in adipose tissue, the HC meal increased LPL activity at 1, 2 and 4 h relative to the basal period. Although there were no consistent effects of meal composition on LPL mass or mRNA in any one tissue, overall LPL mass was generally increased by HC meal-feeding. Because there were meal composition-dependent differences in LPL activity but no detectable differences in mass or mRNA in a particular tissue, LPL regulation by meals seems to be predominately posttranslational.

Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and is described as a "gatekeeper" for its role in partitioning lipoprotein-derived free fatty acids (FFA) between tissues. We have previously demonstrated that muscle-specific overexpression of LPL in mice results in insulin resistance due to decreased muscle glucose uptake. We have now generated a skeletal muscle-specific LPL knockout mouse (SMLPL-/-) to assess the relative impact of muscle LPL on lipid and glucose metabolism. Ablation of LPL activity was limited to the skeletal muscle (predominantly red muscle fibers) as LPL activity in the heart was not affected. At 9 wk of age, there were no differences in body weight or composition between SMLPL-/- and wild-type littermates (SMLPL+/+). Whole body insulin sensitivity, as assessed by hyperinsulinemic (2.5 mU/kg/min)-euglycemic clamps in awake mice, was comparable between SMLPL-/- and SMLPL+/+ with glucose infusion rates (GIR) of 39±4 and 44±4 mg/kg/min, respectively. However, when individual tissues were examined, muscle glucose uptake was significantly increased in SMLPL-/- mice (539±48 vs 341±20 nmol/g/min, p=0.003) but greatly reduced in white adipose tissue (11±3 vs 51±9 nmol/g/min, p=0.003) and heart (1,798±359 vs 3,257±223, p=0.006). SMLPL-/- mice displayed hepatic insulin resistance as indicated by ∼40% suppression of hepatic glucose production during clamps compared to ∼90% suppression in the SMLPL+/+. As the mice aged, SMLPL-/mice at 8-10 mo of age became obese (13.7±0.8 vs 9.4±1.4 g fat mass in SMLPL+/+, p=0.023) and developed systemic insulin resistance with GIR of 14±2 vs 31±7 mg/kg/min in SMLPL+/+ mice. The data suggest that LPL deficiency in the skeletal muscle results in increased insulin sensitivity in muscle, but insulin resistance develops in other organs which may be due to changes in lipid fuel partitioning in non-muscle organs. The mechanism for this compensation remains unclear but the data support that obesity in mice may result from less lipid delivery to skeletal muscle. [ABSTRACT FROM AUTHOR]

Reveals that inhibition of diacylglycerol acyltransferase 1 (DGAT1) may be useful in treating insulin resistance and leptin resistance in human obesity. Information on the tissue lipid analysis; Effects of DGAT1 deficiency on energy and glucose metabolism in Agouti yellow and leptin-deficient mice.

Retinoids, derivatives of vitamin A, induce hypertriglyceridemia through decreased clearance of very low-density lipoprotein by a lipoprotein lipase (LPL)-dependent pathway. The retinoid X receptor (RXR) gamma isotype, which is highly expressed in skeletal muscle, may be important in mediating the effects of retinoids on skeletal muscle metabolism and triglyceride (TG) clearance. RXRgamma-deficient (-/-) mice had lower fasting plasma TG levels compared with wild-type littermates (33.1 +/- 2.0 vs. 51.7 +/- 6.3 mg/dl, respectively; P < 0.05). Skeletal muscle LPL activity was higher in RXRgamma mice (18.7 +/- 2.2 vs. 13.3 +/- 1.3 nmol free fatty acids/min.g; P = 0.03), but LPL activity was not different in adipose and cardiac tissue, suggesting a specific effect of RXRgamma in skeletal muscle. In addition, when exposed to a 14-wk high-fat diet, RXRgamma -/- mice had less weight gain, which was entirely due to lower fat mass (11.9 +/- 1.8 vs. 14.4 +/- 1.1 g; P = 0.01), and leptin levels were also lower in the RXRgamma -/- mice (17.6 +/- 5.0 vs. 30.9 +/- 6.4 ng/ml; P = 0.03). These data suggest that RXRgamma -/- mice are resistant to gain in fat mass in response to high-fat feeding. This occurs, at least in part, through up-regulation of LPL activity in skeletal muscle. An understanding of the mechanisms governing the role of RXR in TG disposal and metabolism may lead to the rational design of RXR-selective agonists and antagonists that may be useful in common disorders such as dyslipidemia and obesity.