Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia

Abstract

The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.

Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice

“…However, it is unclear whether the acute central administration of n-6 PUFA modulates the ability of central leptin to regulate hepatic glucose and lipid metabolism. Consistent with previous studies [16,46], hepatic gluconeogenesis, glucose transportation, and glycolysis were inhibited by central leptin administration in the present study. Furthermore, this study shows that ARA treatment reversed the effect of leptin in suppressing these hepatic glucose metabolism processes.…”

“…For instance, leptin administration in rodents enhances insulin mediated suppression of hepatic glucose production [14,15] and suppress [16] hepatic gluconeogenesis. Moreover, a large amount of evidence supports direct improving function of leptin in peripheral lipid metabolism by regulating lipogenesis, b-oxidation, and cholesterol metabolism [17,18].…”

The role of leptin in diabetes: metabolic effects

“…In support of this, leptin administration directly into the brain, at doses that have no effect when administered peripherally, normalises blood glucose levels in rodent models of uDM [19][20][21][22]. This glucose-lowering effect of leptin occurs via a mechanism that is independent of reduced food intake, increased urinary glucose loss or recovery of pancreatic beta cells.…”

“…This glucose-lowering effect of leptin occurs via a mechanism that is independent of reduced food intake, increased urinary glucose loss or recovery of pancreatic beta cells. Moreover, this glucose-lowering effect of leptin occurs via an insulinindependent mechanism characterised by a normalisation of hepatic glucose production (HGP) and increased rates of glucose uptake in peripheral tissues, including brown adipose tissue, muscle and heart [20]. Collectively, these data establish that leptin signalling in the brain in uDM has the capacity to normalise diabetic hyperglycaemia.…”

“…Recent findings suggest that hyperglucagonaemia is required for diabetic hyperglycaemia, since glucagon receptor null (Gcgr −/− )-mice fail to develop streptozotocin (STZ; a beta cell toxin)-induced diabetes mellitus (STZ-DM) [30], an effect reversed by restoration of glucagon receptor signalling to the liver [31]. Furthermore, evidence suggests that the glucose-lowering effects of leptin in uDM are accompanied by a normalisation of plasma glucagon levels [17,19,20].…”