Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons

Abstract

Insulin receptor substrate 2 (IRS2) is one of three major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake and glucose regulation is unclear. We tested if genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure (BP) and heart rate (HR) and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 µg/kg/min) for 7 days. Compared to control IRS2flox/flox mice, IRS2/POMC-cre mice had similar body weight and food intake (33±1 vs. 35±1g and 3.6±0.5 vs. 3.8±0.2 g/day) but higher MAP and HR (110±2 vs. 102±2 mmHg and 641±9 vs. 616±5 bpm). IRS2/Nestin-cre mice were heavier (38±2 g), slightly hyperphagic (4.5±1.0 g/day), and had higher MAP and HR (108±2 mmHg and 659±9 bpm) compared to control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2flox/flox as well as in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the CNS, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects.

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

“…These chronic effects of hyperleptinemia on SNS activity and blood pressure regulation require an intact POMC neuron-MC4R axis; the ability of leptin to raise blood pressure requires both leptin receptors and MC4R in POMC neurons [152, 163, 164]. Recent work suggests that IRS2 signaling in POMC neurons is essential for the chronic actions of leptin to raise mean arterial pressure [165] .…”

Deletion of Protein Kinase C λ in POMC Neurons Predisposes to Diet-Induced Obesity

“…In leptin receptor–deficient mice in which leptin signaling has been restored exclusively in POMC neurons, amelioration of the obese phenotype is modest, yet insulin sensitivity returns to WT levels (42,43). Likewise, deletion of the leptin receptor from POMC neurons disrupts glucose homeostasis but does not affect leptin-mediated anorexia (44). In addition, a variety of POMC neuron–specific KOs have exclusively glucose-related phenotypes (Lkb1 [45], GLP2 [46], S6K [47]).…”

Insulin action in the brain: Roles in energy and glucose homeostasis

“…IRS‐2 is more abundantly expressed than IRS‐1 within the brain and is particularly abundant in the hypothalamus . Brain‐specific deletion of IRS‐2 results in increased adiposity, hyperphagia, hypertension, hyperinsulinaemia and insulin resistance and these effects are mediated, at least in part, by neurones expressing leptin receptors (LepRb) . IRS‐4 is also expressed within the hypothalamus; however, IRS‐4‐null mice exhibit only a mild metabolic phenotype .…”

“…Similar inducible approaches may be required to explore the roles of AgRP and POMC IR signalling in energy homeostasis. It is worthwhile noting that conditional deletion of IRS‐2 in the whole brain or specifically in POMC neurones promotes marked increases in adiposity …”