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

Abstract

Aims/hypothesis Leptin has profound glucose-lowering effects in rodent models of type 1 diabetes, and is currently being tested clinically to treat this disease. In addition to reversing hyperglycaemia, leptin therapy corrects multiple lipid, energy and neuroendocrine imbalances in rodent models of type 1 diabetes, yet the precise mechanism has not been fully defined. Thus, we performed metabolic analyses to delineate the downstream metabolic pathway mediating leptin-induced glucose lowering in diabetic mice. Methods Mice were injected with streptozotocin (STZ) to induce insulin-deficient diabetes, and were subsequently treated with 20 μg/day recombinant murine leptin or vehicle for 5 to 14 days. Energy-yielding substrates were measured in the liver and plasma, and endogenous glucose production was assessed by tolerance to extended fasting. Results STZ-leptin-treated mice developed severe hypoketotic hypoglycaemia during prolonged fasting, indicative of suppressed endogenous ketone and glucose production. STZ-leptin mice displayed normal gluconeogenic and glycogenolytic capacity, but had depleted circulating glycerol and NEFA. The depletion of glycerol and NEFA correlated tightly with the kinetics of glucose lowering in response to chronic leptin administration, and was not mimicked by single leptin injection. Administration of glycerol acutely reversed fasting-induced hypoglycaemia in leptin-treated mice. Conclusions/interpretation The findings of this study suggest that the diminution of circulating glycerol reduces endogenous glucose production, contributing to severe fastinginduced hypoglycaemia in leptin-treated rodent models of type 1 diabetes, and support that depletion of glycerol contributes to the glucose-lowering action of leptin.

The glucoregulatory actions of leptin

“…Recent evidence suggests that whole body lipolysis resulting in fatty acid and glycerol release may influence hepatic glucose output and play a role in the glucose lowering effect of leptin [19] , [62] , [134] . However, the effect of leptin on lipolysis differs substantially between lean and ob / ob mice compared to insulin-deficient diabetic mice.…”

“…Fifth, rodents and humans with lipodystrophy accompanied by loss of fat tissue and extremely low leptin levels also exhibited hyperglycemia, hyperinsulinemia, and insulin resistance which were corrected by leptin therapy [57] , [58] , [59] . Lastly, insulin deficient rodents, which had depleted white adipose tissue (WAT) depots, exhibited hyperglycemia, insulin resistance, and impaired glucose tolerance, all of which were normalized by leptin therapy [19] , [20] , [60] , [61] , [62] , [63] , [64] , [65] , [66] . Together, these findings demonstrate that leptin signaling can influence glucose regulation independent of its effects on body weight.…”

The role of autonomic efferents and uncoupling protein 1 in the glucose-lowering effect of leptin therapy

“…Although the ANS does not appear to be critical for leptin action in insulin-deficient diabetes, by accessing the CNS peripherally administered leptin may lower blood glucose through a neuroendocrine mechanism. Suppression of hypothalamic pituitary adrenal (HPA) axis activity has been implicated as a potential mechanism of leptin-mediated glucose-lowering in uncontrolled diabetes [47] , although recent evidence suggests the lowering of corticosterone is neither necessary nor sufficient for leptin's anti-diabetic effect [48] , [49] . The hypothalamic pituitary thyroid axis is also a candidate mechanism, although administration of thyroid hormone does not mimic the action of leptin in diabetic rats [31] .…”

Leptin Receptors in RIP-Cre25Mgnneurons Mediate Anti-Dyslipidemia Effects of Leptin in Insulin-Deficient Male Mice

“…Leptin can improve dyslipidemia in insulin-deficient rodents Perry et al, 2014;Wang et al, 2010). Recent studies have pinpointed that improvements of aberrant fat metabolism contributes to glucose-lowering effects of leptin in insulin-deficient rodents (Denroche et al, 2015;Perry et al, 2017;Perry et al, 2014). For instance, administration of fatty acid emulsion into bloodstream (Perry et al, 2014) or i.p.…”

“…For instance, administration of fatty acid emulsion into bloodstream (Perry et al, 2014) or i.p. glycerol injection (Denroche et al, 2015) can reverse glucose-lowering effects of leptin in insulin-deficient rodents. Excess lipids in blood disrupts hepatic glucose metabolism, leading to excess hepatic glucose production (Perry et al, 2017).…”