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-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- 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-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- 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-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.

IntroductionBecause obesity results from an imbalance between energy input and output, with most of the excess calories stored as triglycerides (or triacylglycerols), inhibition of triglyceride synthesis may prevent or reverse obesity (1). One of the key enzymes in triglyceride synthesis is acyl coenzyme A:diacylglycerol acyltransferase (acyl CoA:diacylglycerol acyltransferase, or DGAT), which catalyzes the final step in mammalian triglyceride synthesis. Two DGAT enzymes (DGAT1 and DGAT2) have been identified (2, 3). DGAT1 activity is widely distributed, and its gene (Dgat1) is expressed in all tissues examined (2). To investigate the effects of disrupting triglyceride synthesis on energy and glucose metabolism, we generated DGAT1-deficient (Dgat1 -/-) mice (4). Dgat1 -/-mice have triglycerides in their adipose tissue and normal plasma triglyceride levels. The residual triglyceride synthesis presumably occurs through the actions of DGAT2 and perhaps additional mechanisms of triglyceride synthesis (5). Dgat1 -/-mice are resistant to diet-induced obesity because of increased energy expenditure. This increase is partially mediated by a twofold increase in physical activity in Dgat1 -/-mice fed a high-fat diet. These mice also tend to have enhanced glucose disposal after a glucose load on either a chow or a high-fat diet (4).How does DGAT1 deficiency affect energy and glucose metabolism? One plausible mechanism is by modulating tissue triglyceride metabolism. Increased triglyceride content in tissues such as skeletal muscle and liver correlates with insulin resistance (6-8). Moreover, increased adiposity is associated with resistance to leptin, an adipocyte-derived hormone that enhances energy expenditure and insulin sensitivity (9, 10). Because DGAT1 deficiency in mice is not associated with a compensatory increase in DGAT2 mRNA expression (3), we hypothesized that Dgat1 -/-mice have reduced levels of tissue triglycerides and that these reductions are associated with increased sensitivity to insulin and to leptin. To test this hypothesis, we measured tissue triglyceride levels in Dgat1 -/-mice, and we performed hyperinsulinemic-euglycemic clamp and leptin infusion studies. We also studied the effects of DGAT1 deficiency on energy and glucose metabolism in agouti yellow (A Y /a) and leptindeficient (ob/ob) mice, two genetic models of obesity and insulin resistance. Our findings provide new insights into how alterations in triglyceride synthesis affect insulin and leptin sensitivity. MethodsMice. Dgat1 -/-mice (∼95% C57BL/6 and 5% 129/SvJae background) were generated previously (4). Wild-type (Dgat1 +/+ ), ob/+, and A Y /a mice (all in C57BL/6 background) were from the The Jackson Laboratory (Bar Harbor, Maine, USA). A Y /a mice are obese and insulin resistant, reflecting the antagonism of melanocyte- Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in mammalian triglyceride synthesis. DGAT1-deficient mice are resistant to diet-induced obesity thro...

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CCAAT/enhancer-binding protein ␤ (C/EBP␤) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBP␤ in hepatic lipogenesis remains undefined. Here we show that C/EBP␤ inactivation in Lepr db/db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBP␤ ؊/؊ x Lepr db/db mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBP␤ deletion in Lepr db/db mice down-regulated peroxisome proliferator-activated receptor ␥2 (PPAR␥2) and stearoyl-CoA desaturase-1 and up-regulated PPAR␣ independent of SREBP1c. Conversely, C/EBP␤ overexpression in wild-type mice increased PPAR␥2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBP␤ or C/EBP␤ RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPAR␥2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBP␤ expression in hepatocytes, whereas fatty acids up-regulate C/EBP␤ expression. These data provide novel evidence linking C/EBP␤ expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.Obesity is the most common nutritional disorder in Western societies. Today in the United States, more than 60% of people are either overweight (body mass index (BMI) Ͼ 25) or obese (BMI Ͼ 30) (1). Obesity is frequently associated with type II diabetes, hypertension, and hyperlipidemia, all known risk factors for cardiovascular disease (2). Obesity is also a major risk factor for non-alcoholic fatty liver disease, one of the most common emerging liver diseases in Western countries coinciding with the worldwide obesity epidemic (3, 4). The underlying transcriptional events that contribute to obesity and its associated disorders are not well understood. Some of the genes that regulate body weight have been identified as well as additional neuropeptides, hormones, and nutritional factors that play a role in body weight regulation, particularly through the ␤-adrenergic system (5, 6). Discovery of the hormone leptin and its receptors, which suppress appetite and reduce fat mass, has dramatically increased our understanding of the regulation of energy balance (7,8). More recently, the study of specific transcription factor genes and their metabolism has provided powerful new tools for understanding the integrated mechanisms underlying obesity and diabetes (9 -11). This is most elegantly illustrated using tissue-specific gene knockouts and overexpression models to elucidate the mechanism of action of the PPAR 5 family of nuclear hormone receptors (12). The CCAAT/enhancer-binding protein (C/EBP) family includes five nuclear transcription factors, C/EBP ␣, ␤, ␥, ␦, and ⑀, encoded by separate genes located on different chromosomes (13,14). Collectively, C/EBPs are expressed across a variety of cell types, and...