Shp2 signaling in POMC neurons is important for leptin's actions on blood pressure, energy balance, and glucose regulation

Abstract

Previous studies showed that Src homology-2 tyrosine phosphatase (Shp2) is an important regulator of body weight. In this study, we examined the impact of Shp2 deficiency specifically in proopiomelanocortin (POMC) neurons on metabolic and cardiovascular function and on chronic blood pressure (BP) and metabolic responses to leptin. Mice with Shp2 deleted in POMC neurons (Shp2/Pomc-cre) and control mice (Shp2(flox/flox)) were implanted with telemetry probes and venous catheters for measurement of mean arterial pressure (MAP) and leptin infusion. After at least 5 days of stable control measurements, mice received leptin infusion (2 μg·kg(-1)·day(-1) iv) for 7 days. Compared with Shp2(flox/flox) controls, Shp2/Pomc-cre mice at 22 wk of age were slightly heavier (34 ± 1 vs. 31 ± 1 g) but consumed a similar amount of food (3.9 ± 0.3 vs. 3.8 ± 0.2 g/day). Leptin infusion reduced food intake in Shp2(flox/flox) mice (2.6 ± 0.5 g) and Shp2/Pomc-cre mice (3.2 ± 0.3 g). Despite decreasing food intake, leptin infusion increased MAP in control mice, whereas no significant change in MAP was observed in Shp2/Pomc-cre mice. Leptin infusion also decreased plasma glucose and insulin levels in controls (12 ± 1 to 6 ± 1 μU/ml and 142 ± 12 to 81 ± 8 mg/100 ml) but not in Shp2/Pomc-cre mice. Leptin increased V̇o2 by 16 ± 2% in controls and 7 ± 1% in Shp2/Pomc-cre mice. These results indicate that Shp2 signaling in POMC neurons contributes to the long-term BP and antidiabetic actions of leptin and may play a modest role in normal regulation of body weight.

Leptin as a Mediator of Obesity-Induced Hypertension

“…Thus, the ERK1/2 pathway appears to be more important for metabolic processes such as thermogenesis, as opposed to leptin’s cardiovascular sympathetic effects. However, deletion of the protein tyrosine phosphatase Shp2 which is upstream to the ERK1/2 signaling from the forebrain or POMC neurons not only prevented the anorectic effects of leptin but also attenuated its pressor effect [64, 65]. While Shp2 regulates a number of intracellular processes with respect to leptin signaling it is generally recognized as a critical component of the ERK1/2 pathway, indicating that ERK1/2 may not exclusively regulate the metabolic effects of leptin.…”

Obesity-Induced Hypertension: Brain Signaling Pathways

“…SHP2 deletion in forebrain neurons also attenuated leptin’s ability to reduce food intake and raise BP [72]. We also found that SHP2 signaling in POMC neurons contributes to the chronic BP and glucose-lowering effects of leptin but plays only a modest role in body weight regulation [73••], suggesting that SHP2 in POMC neurons may also contribute to the effects of leptin on SNS activity and BP. IRS2-PI3K signaling may also mediate leptin’s effect on SNS activity and BP.…”

SHP2: a possible target of interest in obesity and its metabolic complications?

“…Ces effets identifiés in vitro ont été confirmés in vivo, la perte d'expression de SHP2 au niveau neuronal chez la souris conduisant à une hyper-activation de la voie JAK2/STAT3 et à une hypoactivation de Erk1/2 en réponse à la leptine dans l'hypothalamus [30]. Le lien entre SHP2 et l'action anorexigène de la leptine a été renforcé in vivo, la délétion de SHP2 au niveau neuronal dans plusieurs modèles murins conduisant à une hyperphagie associée à une obésité, un diabète et une résis-tance à la leptine, par des mécanismes moléculaires encore mal compris [31,32].…”