Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling

Abstract

Objective Although the hypothalamus is crucial for peripheral metabolism control, the signals in specific neurons involved remain poorly understood. The aim of our current study was to explore the role of the hypothalamic gene mothers against decapentaplegic homolog 7 (Smad7) in peripheral glucose disorders. Methods We studied glucose metabolism in high-fat diet (HFD)-fed mice and middle-aged mice with Cre-mediated recombination causing 1) overexpression of Smad7 in hypothalamic proopiomelanocortin (POMC) neurons, 2) deletion of Smad7 in POMC neurons, and 3) overexpression of protein kinase B (AKT) in arcuate nucleus (ARC) in Smad7 overexpressed mice. Intracerebroventricular (ICV) cannulation of insulin was used to test the hypothalamic insulin sensitivity in the mice. Hypothalamic primary neurons were used to investigate the mechanism of Smad7 regulating hypothalamic insulin signaling. Results We found that Smad7 expression was increased in POMC neurons in the hypothalamic ARC of HFD-fed or middle-aged mice. Furthermore, overexpression of Smad7 in POMC neurons disrupted the glucose balance, and deletion of Smad7 in POMC neurons prevented diet- or age-induced glucose disorders, which was likely to be independent of changes in body weight or food intake. Moreover, the effect of Smad7 was reversed by overexpression of AKT in the ARC. Finally, Smad7 decreased AKT phosphorylation by activating protein phosphatase 1c in hypothalamic primary neurons. Conclusions Our results demonstrated that an excess of central Smad7 in POMC neurons disrupts glucose balance by attenuating hypothalamic insulin signaling. In addition, we found that this regulation was mediated by the activity of protein phosphatase 1c.

HypothalamicHnscrregulates glucose balance by mediating central inflammation and insulin signal

“…Two main populations of neurons, POMC and AgRP, express leptin receptor and insulin receptor, 23,24 and insulin action in these neurons affected systematic insulin resistance. 25 Inhibition of AKT phospholation in POMC neurons induced age-and diet-related insulin resistance, [26][27][28] while, increasing PI3K activity, the upstream of AKT, in POMC neurons improved insulin and glycemic responses. 29 Thus, we would investigate the implicated neurons in following studies.…”

Gabra5 plays a sexually dimorphic role in POMC neuron activity and glucose balance

“…For example, when glucose-sensing of glucose excitatory POMC neurons is impaired, male mice develop glucose intolerance with unchanged body weight ( 9 ). Overexpression or deletion of Mothers against decapentaplegic homolog 7 (SMAD7) in POMC neurons changed glucose balance without affecting the feeding behavior or body weight balance in male mice ( 46 ). Male mice with POMC-specific deletion of inositol-requiring enzyme 1 (IRE1α) showed attenuated leptin and insulin response in POMC neurons and developed glucose intolerance despite normal body weight on chow diet ( 47 ).…”

Sirtuin 6 supra‐physiological overexpression in hypothalamic pro‐opiomelanocortin neurons promotes obesity via the hypothalamus‐adipose axis

“…Immunofluorescence staining in the brain was as previously described 23 . Briefly, mice were anesthetized and transcardially perfused with PBS, then 4% paraformaldehyde (PFA).…”