Leptin Engages a Hypothalamic Neurocircuitry to Permit Survival in the Absence of Insulin

Abstract

Summary The dogma that life without insulin is incompatible has recently been challenged by results showing viability of insulin-deficient rodents undergoing leptin mono-therapy. Yet, the mechanisms underlying these actions of leptin are unknown. Here, the metabolic outcomes of intracerebroventricular (icv) administration of leptin in mice devoid of insulin and lacking or re-expressing leptin receptors (LEPRs) only in selected neuronal groups were assessed. Our results demonstrate that concomitant re-expression of LEPRs only in hypothalamic γ-aminobutyric acid (GABA)ergic and pro-opiomelanocortin (POMC) neurons is sufficient to fully mediate the life-saving and anti-diabetic actions of leptin in insulin deficiency. Our analyses indicate that enhanced glucose uptake by brown adipose tissue and soleus muscle, as well as improved hepatic metabolism, underlie these effects of leptin. Collectively, our data elucidate a hypothalamic-dependent pathway enabling life without insulin and hence pave the way for developing better treatments for diseases of insulin deficiency.

Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol

“…Interestingly, although the Perry et al study implicated the suppression of corticosterone in the glucose-lowering effect of leptin [11], we observed a robust elevation of plasma corticosterone during fasting hypoglycaemia in STZ-leptin mice, indicating that the hypoglycaemic effect of leptin during fasting is at least partly independent of corticosterone suppression. Alternatively, leptin can stimulate glucose uptake in the peripheral tissues of rodent models of type 1 diabetes [6,7]. However, glucose utilisation in white adipose and some skeletal muscle groups is unaltered in response to leptin [6,7], and other studies report that glucose uptake or disposal is not substantially augmented by leptin therapy [1,4].…”

“…Several mechanisms have been proposed for this glucose-lowering action, including suppressed glucagon and improved insulin sensitivity [1][2][3][4][5], and central leptin therapy was shown to inhibit hepatic glucose production [6] and enhance glucose uptake in brown adipose tissue [7]. With the plethora of metabolic changes that occur with leptin administration in rodent models of type 1 diabetes, the precise mechanism of leptin action in type 1 diabetes remains unclear.…”

The role of leptin in diabetes: metabolic effects

“…leptin administration failed to normalise blood glucose levels in leptin receptor-deficient mice in which leptin receptors were re-expressed in pro-opiomelanocortin (POMC) neurons [53]. By contrast, re-expression of leptin signalling to both γ-aminobutyric acid (GABA) and POMC neurons in otherwise leptin receptor-deficient mice is sufficient to mediate the majority of the glucose-lowering effects of leptin [53]. Future studies are further warranted to better characterise and understand the neurons and neurocircuits that mediate the glucose-lowering and other neuroendocrine effects of leptin in uDM.…”

Hypothalamic control of glucose and lipid metabolism in skeletal muscle

“…These effects on skeletal muscle are mediated by sympathetic nerves innervating the tissue. Leptin has recently been shown to correct hyperglycemia associated with lipodystrophy or insulin-deficient diabetes 15) , with hypothalamic GABAergic neurons appearing to be the target for this action of leptin 55) . More recently, a single injection of FGF1 into the lateral ventricle was shown to induce a sustained reduction in blood glucose level associated with increased glucose uptake in skeletal muscle and the liver in several rodent models of type 2 diabetes 16) .…”

“…Unexpectedly, however, examination of mice in which the leptin receptor gene was deleted specifically in SF1 neurons revealed that leptin signaling in these VMH neurons was not required for the normalization of diabetic hyperglycemia by central leptin infusion 54) . The role of other hypothalamic neurons in the leptin-induced normalization of hyperglycemia in insulin-deficient diabetes was further studied in mice in which Ob-Rb expression was genetically manipulated in such neurons 55) . Leptin signaling in γ-aminobutyric acid (GABA)-expressing neurons and consequent suppression of their activity were found to be necessary for the leptin-induced correction of diabetic hyperglycemia in mice with STZ-induced diabetes.…”