We directly examined whether visceral fat (VF) modulates hepatic insulin action by randomizing moderately obese (body wt approximately 400 g) Sprague-Dawley rats to either surgical removal of epididymal and perinephric fat pads (VF-; n = 9) or a sham operation (VF+; n = 11). Three weeks later, total VF was fourfold increased (8.5 +/- 1.2 vs. 2.1 +/- 0.3 g, P < 0.001) in the VF+ compared with the VF- group, but whole-body fat mass (determined using 3H2O) was not significantly different. The rates of insulin infusion required to maintain plasma glucose levels and basal hepatic glucose production in the presence of hepatic-pancreatic clamp were markedly decreased in VF- compared with VF+ rats (0.57 +/- 0.02 vs. 1.22 +/- 0.19 mU x kg(-1) x min(-1), P < 0.001). Similarly, plasma insulin levels were more than twofold higher in the VF+ group (P < 0.001). The heightened hepatic insulin sensitivity is supported by the decrease in gene expression of both glucose-6-phosphatase and PEPCK and by physiological hyperinsulinemia in VF- but not VF+ rats. The improvement in hepatic insulin sensitivity in VF- rats was also supported by a approximately 70% decrease in the plasma levels of insulin-like growth factor binding protein-1, a marker of insulin's transcription regulation in the liver. The removal of VF pads also resulted in marked decreases in the gene expression of tumor necrosis factor-alpha (by 72%) and leptin (by 60%) in subcutaneous fat. We conclude that visceral fat is a potent modulator of insulin action on hepatic glucose production and gene expression.

Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance.

Long term administration of leptin decreases caloric intake and fat mass and improves glucose tolerance. Here we examine whether leptin acutely regulates peripheral and hepatic insulin action. Recombinant mouse leptin (0.3 mg/kg⅐h, Leptin ؉) or vehicle (Leptin ؊) were administered for 6 h to 4-month-old rats (n ‫؍‬ 20), and insulin (3 milliunits/kg⅐min) clamp studies were performed. During physiologic hyperinsulinemia (plasma insulin ϳ65 microunits/ml), the rates of whole body glucose uptake, glycolysis, and glycogen synthesis and the rates of 2-deoxyglucose uptake in individual tissues were similar in Leptin ؊ and Leptin ؉. Post-absorptive hepatic glucose production (HGP) was similar in the two groups. However, leptin enhanced insulin's inhibition of HGP (4.1 ؎ 0.7 and 6.2 ؎ 0.7 mg/kg⅐min; p < 0.05). The decreased HGP in the Leptin ؉ group was due to a marked suppression of hepatic glycogenolysis (0.7 ؎ 0.1 versus 4.1 ؎ 0.6 mg/kg⅐min, in Leptin ؉ versus Leptin ؊, respectively; p < 0.001), whereas the % contribution of gluconeogenesis to HGP was markedly increased (82 ؎ 3% versus 36 ؎ 4% in Leptin ؉ and Leptin ؊, respectively; p < 0.001). At the end of the 6-h leptin infusion, the hepatic abundance of glucokinase mRNA was decreased, whereas that of phosphoenolpyruvate carboxykinase mRNA was increased compared with Leptin ؊. We conclude that an acute increase in plasma leptin 1) enhances insulin's ability to inhibit HGP, 2) does not affect peripheral insulin action, and 3) induces a redistribution of intrahepatic glucose fluxes and changes in the gene expression of hepatic enzymes that closely resemble those of fasting.The recent discovery of the ob gene (1) and preliminary analysis of the properties of its product, leptin (2-7), have shed new light on the regulation of energy homeostasis (8). Since the most common alteration in energy balance, obesity, is tightly associated with insulin resistance, it has been proposed that leptin may play a role in carbohydrate metabolism and insulin action (8 -11). Indeed, recent work in cultured adipose cells (12, 13) and hepatocytes (9) has suggested that leptin may antagonize insulin action in these cells. Conversely, early work on the effect of exogenous leptin in ob/ob mice had demonstrated a marked decrease in both plasma insulin and glucose concentrations following prolonged administration of this protein (2,4,5,7,14,15). Since the decline in plasma glucose and insulin was greater in leptin-treated mice than in pair-fed control mice (2, 14), it has been proposed that leptin may directly or indirectly improve in vivo insulin action.However, it is well established that changes in food intake, body weight, fat mass and/or fat distribution similar to those associated with long term leptin administration can independently alter insulin action, particularly in insulin-resistant and obese animal models (16,17). Thus, it is presently unknown whether the short term administration of exogenous leptin modulates insulin's ability to promote glucose disposal and/or to regulate hepat...

Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and α-cell function and number are incompletely understood. To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-specific deletion of the glucagon receptor. GcgrHep−/− mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr−/− mice. Despite preservation of islet Gcgr signaling, GcgrHep−/− mice developed hyperglucagonemia and α-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates α-cell mass, wild-type islets were transplanted into Gcgr−/− or GcgrHep−/− mice. Wild-type islets beneath the renal capsule of Gcgr−/− or GcgrHep−/− mice exhibited an increased rate of α-cell proliferation and expansion of α-cell area, consistent with changes exhibited by endogenous α-cells in Gcgr−/− and GcgrHep−/− pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating α-cell proliferation and mass may facilitate the generation and expansion of α-cells for transdifferentiation into β-cells and the treatment of diabetes.