Pannexins (Panxs), large-pore channel forming glycoproteins, are expressed in a wide variety of tissues including the skin, bone, and cochlea. To date, the use of single knockout mouse models of both Panx1 and Panx3 have demonstrated their roles in skin development, bone formation, and auditory phenotypes. Due to sequence homology between Panx1 and Panx3, when one Panx is ablated from germline, the other may be upregulated in a compensatory mechanism to maintain tissue homeostasis and function. To evaluate the roles of Panx1 and Panx3 in the skin, bone, and cochlea, we created the first Panx1/Panx3 double knockout mouse model (dKO). These mice had smaller litters and reduced body weight compared to wildtype controls. The dKO dorsal skin had decreased epidermal and dermal area as well as decreased hypodermal area in neonatal but not in older mice. In addition, mouse skull shape and size were altered, and long bone length was decreased in neonatal dKO mice. Finally, auditory tests revealed that dKO mice did not exhibit hearing loss and were even slightly protected against noise-induced hearing damage at mid-frequency regions. Taken together, our findings suggest that Panx1 and Panx3 are important at early stages of development in the skin and bone but may be redundant in the auditory system. Key messages & Panx double KO mice had smaller litters and reduced body weight. & dKO skin had decreased epidermal and dermal area in neonatal mice. & Skull shape and size changed plus long bone length decreased in neonatal dKO mice. & dKO had no hearing loss and were slightly protected against noise-induced damage.

Obesity and elevation of circulating free fatty acids are associated with an accumulation and proinflammatory polarization of macrophages within metabolically active tissues, such as adipose tissue, muscle, liver, and pancreas. Beyond macrophages, neutrophils also accumulate in adipose and muscle tissues during high-fat diets and contribute to a state of local inflammation and insulin resistance. However, the mechanisms by which neutrophils are recruited to these tissues are largely unknown. Here we used a cell culture system as proof of concept to show that, upon exposure to a saturated fatty acid, palmitate, macrophages release nucleotides that attract neutrophils. Moreover, we found that palmitate up-regulates pannexin-1 channels in macrophages that mediate the attraction of neutrophils, shown previously to allow transfer of nucleotides across membranes. These findings suggest that proinflammatory macrophages release nucleotides through pannexin-1, a process that may facilitate neutrophil recruitment into metabolic tissues during obesity.

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Pannexin 3 (PANX3), a channel-forming glycoprotein, facilitates nutrient-induced inflammation in vitro, and genetic linkage data suggest that it regulates body mass index. In this study, we characterized global Panx3 knockout (KO) mice in the context of forced exercise (FEX) and high fat diet (HFD). Wildtype (WT) mice placed on either a western diet or a HFD showed increased expression of Panx3 mRNA and protein in adipose tissue, while FEX reduced its expression. We did not observe any overt differences between WT and Panx3 KO female mice; however, sedentary (SED) Panx3 KO male mice fed a chow diet had lower body weight and lower fat mass from 12 weeks that persisted until 30 weeks of age compared to SED WT. Remarkably, the body weight and fat mass reduction in Panx3 KO mice was similar in magnitude to the effect of 6 weeks of FEX in WT mice. Additionally, Panx3 KO mice demonstrated lower inflammatory status in white adipose tissue compared to SED and FEX WT mice. When challenged with a HFD, male Panx3 KO mice exhibited less weight gain and lower inflammatory status in quadriceps muscle and white adipose tissue. These data suggest that Panx3 regulates fat accumulation and inflammation in white adipose and skeletal muscle tissue of male mice and may act as a molecular switch that is controlled by nutrients and exercise.