Leptin and insulin are key hormones inferring metabolic status to the brain and are essential in maintaining energy homeostasis. Leptin and insulin are sensed via leptin and insulin receptors primarily on first order POMC or AgRP neurons in the arcuate nucleus of the hypothalamus (ARC). Downstream signaling of these receptors is regulated by protein tyrosine phosphatases (PTPs), particular PTP1B and TCPTP. PTP1B & TCPTP attenuate leptin signaling in the brain, however the precise neuronal populations in which PTP1B and TCPTP exert their effects remain unknown.

As POMC neurons represent one of the first neuronal subsets to sense peripheral insulin and leptin we first determined whether TCPTP was expressed in POMC neurons. We utilized immunohistochemistry and assessed TCPTP versus GFP expression in the hypothalami of Pomc-GFP transgenic mice. TCPTP protein was detected in roughly 40-60% of all POMC neurons in the ARC with co-localisation predominating in the medial-caudal ARC.

In an attempt to understand the relative contribution of these PTPs in the context of obesity we use Cre-lox technology to conditionally knock out PTP1B (POMC-1B), TCPTP (POMC-TC) or both (POMC-DKO) specifically in POMC neurons. Body weights were not overtly altered in POMC-TC or POMC-1B, however POMC-TC showed an increase in insulin sensitivity whereas POMC-1B mice showed an increase in leptin sensitivity. Interestingly in POMC-DKO we found increases in both insulin and leptin sensitivity along with marked reductions in body weight and adiposity. Furthermore POMC DKO mice fed a high energy diet were protected from the development of obesity and the associated insulin resistance, glucose intolerance and hepatosteatosis.

Our results indicate that PTP1B and TCPTP differentially contribute to leptin and insulin signaling in POMC neurons and act synergistically to control energy homeostasis.