Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling

OBJECTIVE

Leptin therapy has been found to reverse hyperglycemia and prevent mortality in several rodent models of type 1 diabetes. Yet the mechanism of leptin-mediated reversal of hyperglycemia has not been fully defined. The liver is a key organ regulating glucose metabolism and is also a target of leptin action. Thus we hypothesized that exogenous leptin administered to mice with streptozotocin (STZ)-induced diabetes reverses hyperglycemia through direct action on hepatocytes.

RESEARCH DESIGN AND METHODS

After the induction of diabetes in mice with a high dose of STZ, recombinant mouse leptin was delivered at a supraphysiological dose for 14 days by an osmotic pump implant. We characterized the effect of leptin administration in C57Bl/6J mice with STZ-induced diabetes and then examined whether leptin therapy could reverse STZ-induced hyperglycemia in mice in which hepatic leptin signaling was specifically disrupted.

RESULTS

Hyperleptinemia reversed hyperglycemia and hyperketonemia in diabetic C57Bl/6J mice and dramatically improved glucose tolerance. These effects were associated with reduced plasma glucagon and growth hormone levels and dramatically enhanced insulin sensitivity, without changes in glucose uptake by skeletal muscle. Leptin therapy also ameliorated STZ-induced hyperglycemia and hyperketonemia in mice with disrupted hepatic leptin signaling to a similar extent as observed in wild-type littermates with STZ-induced diabetes.

CONCLUSIONS

These observations reveal that hyperleptinemia reverses the symptoms of STZ-induced diabetes in mice and that this action does not require direct leptin signaling in the liver.Since the discovery of insulin in 1922 (1), insulin therapy has been the predominant treatment for type 1 diabetes. However, the adipocyte-derived hormone leptin has been found to reverse hyperglycemia and prevent mortality when administered to several rodent models of type 1 diabetes (2–7). Leptin has well known glucose-lowering effects in leptin-deficient ob/ob mice, and has been established as an important regulator of glucose metabolism. Yet it is surprising that leptin can restore euglycemia in insulin-deficient rodents, and the mechanism underlying this effect is unclear.Insulin-deficient diabetes is associated with elevated circulating glucagon levels, which contributes to hyperglycemia (8–11). Interestingly, Yu et al. (2) demonstrated that exogenous leptin can reverse hyperglucagonemia in rats with streptozotocin (STZ)-induced diabetes and in NOD mice; this effect of leptin therapy may contribute to the restoration of euglycemia in these animals. In addition to hyperglucagonemia, insulin resistance is another common characteristic of untreated human and rodent insulin deficiency (12–15). Exogenous leptin can improve insulin sensitivity in rats with STZ-induced diabetes (4,15,16). Therefore the insulin sensitizing effect of leptin may also contribute to lowering blood glucose in type 1 diabetic rodents.The liver is a key organ that controls glucose flux in response to many metabolic cues and is a major regulator of lipid metabolism and ketone body production. Therefore disturbed hepatic nutrient metabolism is likely a major contributor to hyperglycemia, dyslipidemia, and hyperketonemia in insulin-deficient diabetes. Attenuated insulin action on the liver alone contributes to perturbations in glucose homeostasis (17). Leptin has well-known insulin-sensitizing effects on the liver (18–20), and the long signaling leptin receptor isoform (LepRb) is expressed in the liver and hepatic cell lines (19,21). Intriguingly, we and others have found that direct action of leptin on hepatocytes can modulate hepatic insulin action (18,20,22,23).We hypothesized that in mice with STZ-induced diabetes, exogenous leptin may act directly on the liver to lower blood glucose and reverse the metabolic consequences of insulin-deficient diabetes. Peripheral leptin therapy in the STZ-diabetic mouse model has not yet been examined; therefore, to test our hypothesis we first characterized the effect of hyperleptinemia on metabolism in mice with STZ-induced diabetes. After this, we examined whether direct leptin action on the liver is required for the therapeutic effect of leptin therapy in insulin-deficient diabetes by administering exogenous leptin to mice with STZ-induced diabetes that have a hepatic-specific disruption of leptin signaling.