UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia

Abstract

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity — and thus also leptin levels — in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

A pyrexic effect of FGF21 independent of energy expenditure and UCP1

“…Thus, a robust relative induction of UCP1 mRNA by FGF21 was reported to occur in white adipose tissue (WAT), but not in brown adipose tissue (BAT): a 3-fold induction was found in BAT but 5-fold in WAT [ 5 ]; a 2-fold induction was found in BAT but a 20-fold induction in WAT [ 7 ]. That such changes in UCP1 mRNA do not result in observable amounts of UCP1 protein (as demonstrated here) is understandable because the level of UCP1 mRNA in WAT is very low, about 1000-fold lower than in BAT [ 20 , 26 , 54 ] (at thermoneutrality). Thus, even a 20-fold increase could not bring the UCP1 mRNA levels close to those in BAT.…”

“…Subsequently, UCP1 amount per 1 μg total protein or whole adipose tissue depot was recalculated and expressed (i.e. the amount of UCP1 per unit of protein was multiplied by total protein amount in the depot [ 20 ]). Importantly, all band intensities were normalized to the same standard sample loaded to each gel, so the A.U.…”

A neural basis for brain leptin action on reducing type 1 diabetic hyperglycemia

“…It is thus conceivable that an additional leptin dose on top of the mildly reduced leptin level in human T1D may not be able to provide additional beneficial effects. In other words, the beneficial effect of brain leptin action may have been reflected by the effects of insulin treatments 49 . Further studies are warranted to specifically address this possibility.…”

Sexual dimorphism of leptin and adiposity in children between 0 and 10 years: a systematic review and meta-analysis

“…Leptin exerts dichotomous and paradoxical effects on cardiovascular function, in most cases, high leptin levels correlate positively with unfavourable outcomes [ 69 , 70 ], such as decreased arterial distensibility or atherosclerosis, which has been associated with macrovascular diseases, and increased risk of myocardial infarction [ 71 ]. The early dimorphism in which leptin levels are higher in girls may favour the development of alterations in its signalling and the effects [ 72 ].…”