Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes and nonadipocytes to levels far below those of pairfed controls. In cultured pancreatic islets, leptin lowered triglyceride (TG) content by preventing TG formation from free fatty acids (FFA) and by increasing FFA oxidation. In vivo hyperleptinemia, induced in normal rats by adenovirus gene transfer, depleted TG content in liver, skeletal muscle, and pancreas without increasing plasma FFA or ketones, suggesting intracellular oxidation. In islets of obese Zucker Diabetic Fatty rats with leptin receptor mutations, leptin had no effect in vivo or in vitro. The TG content was Ϸ20 times normal, and esterification capacity was increased 3-to 4-fold. Thus, in rats with normal leptin receptors but not in Zucker Diabetic Fatty rats, nonadipocytes and adipocytes esterify FFA, store them as TG, and later oxidize them intracellularly via an ''indirect pathway'' of intracellular fatty acid metabolism controlled by leptin. By maintaining insulin sensitivity and preventing islet lipotoxicity, this activity of leptin may prevent adipogenic diabetes.

In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short-and long-term advantages over insulin monotherapy for type 1 diabetes.glucagon suppression | lipid-lowering | metabolomics | cholesterol regulation | glucose regulation

OBJECTIVETo determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency.RESEARCH DESIGN AND METHODSWe compared pertinent clinical and metabolic parameters in glucagon receptor-null (Gcgr−/−) mice and wild-type (Gcgr+/+) controls after equivalent destruction of β-cells. We used a double dose of streptozotocin to maximize β-cell destruction.RESULTSGcgr+/+ mice became hyperglycemic (>500 mg/dL), hyperketonemic, polyuric, and cachectic and had to be killed after 6 weeks. Despite comparable β-cell destruction in Gcgr−/− mice, none of the foregoing clinical or laboratory manifestations of diabetes appeared. There was marked α-cell hyperplasia and hyperglucagonemia (∼1,200 pg/mL), but hepatic phosphorylated cAMP response element binding protein and phosphoenolpyruvate carboxykinase mRNA were profoundly reduced compared with Gcgr+/+ mice with diabetes—evidence that glucagon action had been effectively blocked. Fasting glucose levels and oral and intraperitoneal glucose tolerance tests were normal. Both fasting and nonfasting free fatty acid levels and nonfasting β-hydroxy butyrate levels were lower.CONCLUSIONSWe conclude that blocking glucagon action prevents the deadly metabolic and clinical derangements of type 1 diabetic mice.

Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of ␤-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within Ϸ10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10 -80 days without other treatment; normal physiological conditions lasted for Ϸ175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-␥-coactivator-1␣ may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.leptin ͉ hyperglucagonemia ͉ glucagon suppression ͉ IGF-1 upregulation ͉ insulinomimetic

We have studied mechanisms by which leptin overexpression, which reduces body weight via anorexic and thermogenic actions, induces triglyceride depletion in adipocytes and nonadipocytes. Here we show that leptin alters in pancreatic islets the mRNA of the genes encoding enzymes of free fatty acid metabolism and uncoupling protein-2 (UCP-2). In animals infused with a recombinant adenovirus containing the leptin cDNA, the levels of mRNAs encoding enzymes of mitochondrial and peroxisomal oxidation rose 2-to 3-fold, whereas mRNA encoding an enzyme of esterification declined in islets from hyperleptinemic rats. Islet UCP-2 mRNA rose 6-fold. All in vivo changes occurred in vitro in normal islets cultured with recombinant leptin, indicating direct extraneural effects. Leptin overexpression increased UCP-2 mRNA by more than 10-fold in epididymal, retroperitoneal, and subcutaneous fat tissue of normal, but not of leptin-receptordefective obese rats. By directly regulating the expression of enzymes of free fatty acid metabolism and of UCP-2, leptin controls intracellular triglyceride content of certain nonadipocytes, as well as adipocytes.Overexpression of leptin, the adipocyte hormone that regulates body composition through its effects on food intake and energy metabolism (1-5), causes the rapid disappearance of all grossly visible body fat, usually within 1 week (6). In addition, the triglyceride (TG) content of nonadipocyte tissues such as the pancreatic islets is profoundly reduced (7). Because these changes in body fat are unaccompanied by an increase in plasma levels of free fatty acids (FFA) and ␤-hydroxybutyrate or by ketonuria, we have concluded that the TG must have undergone internal hydrolysis and oxidation within the individual cells (8). This conclusion is supported by in vitro studies showing that leptin lowers the TG content of isolated islets by reducing esterification and by increasing oxidation of FFA (8). It is also consistent with a report that leptin decreases the mRNA and activity of acetyl-CoA carboxylase (ACC) (9), which would increase mitochondrial oxidation of FFA by lowering its product, malonyl-CoA (10).In this study we examine possible mechanisms by which leptin overexpression reduces the TG content of nonadipocytes and adipocytes to unmeasurable levels. Islets are known to express leptin receptor isoforms (7,11,12). We therefore compared in pancreatic islets isolated from hyperleptinemic rats and from appropriate euleptinemic controls the mRNA levels of enzymes involved in esterification or oxidation of FFA. In addition, to explain the thermogenic effect of leptin, we examined in both islets and white adipose tissue the mRNA of uncoupling proteins (UCP)-1 and -2, proteins believed to play an important role in regulating thermogenesis (13). White adipocytes are also known to express leptin receptors (14). MATERIALS AND METHODSAnimals. Lean wild-type (ϩ͞ϩ) male Zucker diabetic fatty (ZDF) rats and obese homozygous ( fa͞fa) male ZDF rats were bred in our laboratory from [ZDF͞Drt-fa(F10)...