Leptin peptide in diabetes: from mechanism to therapeutics
Type of Award: Spark
Date Awarded: August 2011
Award End Date: July 2013
Amount Awarded: $ 399,597.00
PI(s): Nissim Hay, UIC; Joseph Bass, NU; Graeme Bell, UChicago; Louis Philipson, UChicago;
Abstract: Leptin receptor levels are highest in the brain, which is consistent with the primary action of leptin to decrease food intake. However, we hypothesize that, under normal physiological conditions, leptin also plays a key role in the regulation of blood glucose levels through direct effects on the liver and regulation of hepatic glucose production. This effect is more readily evident in insulin-deficient states, common in both type 1 and late type 2 diabetes. We further propose that insulin modulates leptin signaling as abrogation of insulin signaling increases leptin levels in blood and leptin receptor expression in liver. Although this hypothesis challenges the commonly accepted view that leptin exerts its effects through it action in various regions of the brain, there are other observations that provide support for our hypothesis: 1. Liver-specific insulin receptor knockout mice display a 10-fold increase in serum leptin levels as well as a 35- fold increase in leptin receptor levels mRNA in the liver; 2. The level of hepatic leptin receptor is dramatically increased in mice with liver-specific knockout of the downstream insulin receptor signaling molecules IRS1 and PI3 kinase; 3. The expression of hepatic leptin receptor in Akt-deficient mice is markedly increased (data not shown); and 4. Leptin treatment in human patients with lipodystrophy and in multi-tissue Akt-mutant mice (both of which have low leptin levels) normalizes blood glucose levels. Thus, impaired hepatic insulin/PI3K/Akt signaling in the liver is coupled to a marked elevation of leptin receptor levels concomitant with an increase in the levels of circulating leptin. Moreover, deficiency of leptin due to impaired development and/or function of adipose tissue is linked to hepatic overproduction of glucose, increasing insulin resistance and thereby exacerbating diabetes, and fasting hyperglycemia in particular. Surprisingly, the significance of these observations implicating leptin signaling in the regulation of hepatic function are not fully appreciated and need to be further explored to impact clinical practice. Thus, a major goal of this proposal is to challenge the current dogma that leptin exerts its effect on glucose homeostasis exclusively or largely though its effect on the brain. Specifically we will generate hepatic leptin receptor KO mice. These mice will be treated to induce type 1 diabetes and will be subjected to leptin therapy. These mice will also be crossed with Akita mice and the compound mice will be subjected to leptin therapy.