Pannexin 1 regulates adipose stromal cell differentiation and fat accumulation

Abstract

Pannexin 1 (Panx1) is a channel-forming glycoprotein important in paracrine signaling and cellular development. In this study, we discovered that mice globally lacking Panx1 (KO) have significantly greater total fat mass and reduced lean mass compared to wild type (WT) mice under a normal diet. Despite having higher fat content, Panx1 KO mice on a high fat diet exhibited no differences in weight gain and blood markers of obesity as compared to WT controls, except for an increase in glucose and insulin levels. However, metabolic cage data revealed that these Panx1 KO mice display significantly increased activity levels, higher ambulatory activity, and reduced sleep duration relative to their WT littermates on a high-fat diet. To uncover the cellular mechanism responsible for the increased fat content in the KO, we isolated primary cultures of adipose-derived stromal cells (ASCs) from WT and KO fat pads. In WT ASCs we observed that Panx1 protein levels increase upon induction into an adipogenic lineage. ASCs isolated from Panx1 KO mice proliferate less but demonstrate enhanced adipogenic differentiation with increased intracellular lipid accumulation, glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity, and adipokine secretion, as compared to WT ASCs. This was consistent with the increased adipocyte size and decreased adipocyte numbers observed in subcutaneous fat of the Panx1 KO mice compared to WT. We concluded that Panx1 plays a key role in adipose stromal cells during the early stages of adipogenic proliferation and differentiation, regulating fat accumulation in vivo.

Double deletion of Panx1 and Panx3 affects skin and bone but not hearing

“…At P4, however, this finding was no longer evident and instead dKO mice exhibited increased hypodermal area where subcutaneous fat is found. The Panx1 −/− mice also had a significant increase in hypodermal area and an increase in overall fat content due to the enhanced differentiation capacity of adipose stromal cells from the Panx1 −/− to form adipocytes with higher fat content [40].…”

A Genetic Polymorphism in the Pannexin1 Gene Predisposes for The Development of Endothelial Dysfunction with Increasing BMI

“…Finally, mice with ubiquitous Panx1 deletion have increased fat mass and reduced lean mass [12,13]. This increase in body adiposity is mainly due to larger volumes of subcutaneous and visceral adipose tissues [12] and results in increased glucose and insulin levels [13]. Altogether, these observations suggest strong links between Panx1 channel functionality, metabolism and endothelial function.…”

“…In addition, Panx1 channel activity appeared to contribute to the control of metabolic homeostasis by regulating insulin-stimulated glucose uptake in adipocytes [24]. Finally, mice with ubiquitous Panx1 deletion have increased fat mass and reduced lean mass [12,13]. This increase in body adiposity is mainly due to larger volumes of subcutaneous and visceral adipose tissues [12] and results in increased glucose and insulin levels [13].…”

“…Myocardial perfusion was determined by 13 N-ammonia PET/CT as previously described [17]. Myocardial blood flow (MBF, mL/g/min) was assessed at rest, during a cold pressor test (CPT), and during hyperemia pharmacologically induced with standard infusion of dipyridamole (140 mg/kg/min).…”

“…Moreover, Panx1 deficiency has been shown to be associated with atherosclerosis and white adipose tissue accumulation as well as with lymphatic dysfunction [12]. In mice, Panx1 appeared to control adipose stromal cell proliferation and differentiation, thereby regulating fat accumulation in vivo [13]. Interestingly, a Panx1-400A>C single nucleotide polymorphism (SNP; rs1138800), inducing an amino acid change from a Glutamine to a Histidine (Q5H) in the N-terminus of Panx1, encodes for a gain-of-function channel [14].…”