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Animal Models

Pannexin 3 deletion reduces fat accumulation and inflammation in a sex-specific manner

Abstract

Background

Pannexin 3 (PANX3) is a channel-forming glycoprotein that enables nutrient-induced inflammation in vitro, and genetic linkage data suggest that it regulates body mass index. Here, we characterized inflammatory and metabolic parameters in global Panx3 knockout (KO) mice in the context of forced treadmill running (FEX) and high-fat diet (HFD).

Methods

C57BL/6N (WT) and KO mice were randomized to either a FEX running protocol or no running (SED) from 24 until 30 weeks of age. Body weight was measured biweekly, and body composition was measured at 24 and 30 weeks of age. Male WT and KO mice were fed a HFD from 12 to 28 weeks of age. Metabolic organs were analyzed for a panel of inflammatory markers and PANX3 expression.

Results

In females there were no significant differences in body composition between genotypes, which could be due to the lack of PANX3 expression in female white adipose tissue, while male KOs fed a chow diet had lower body weight and lower fat mass at 24 and 30 weeks of age, which was reduced to the same extent as 6 weeks of FEX in WT mice. In addition, male KO mice exhibited significantly lower expression of multiple pro-inflammatory genes in white adipose tissue compared to WT mice. While on a HFD body weight differences were insignificant, multiple inflammatory genes were significantly different in quadriceps muscle and white adipose tissue resulting in a more anti-inflammatory phenotype in KO mice compared to WT. The lower fat mass in male KO mice may be due to significantly fewer adipocytes in their subcutaneous fat compared to WT mice. Mechanistically, adipose stromal cells (ASCs) cultured from KO mice grow significantly slower than WT ASCs.

Conclusion

PANX3 is expressed in male adult mouse adipose tissue and may regulate adipocyte numbers, influencing fat accumulation and inflammation.

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Fig. 1: Male Panx3 KO mice weigh less, have less fat mass, and more lean mass than WT mice to the same extent as 6 weeks of forced exercise.
Fig. 2: Male Panx3 KO mice have lower inflammatory index in quadriceps and visceral fat tissues compared to WT mice.
Fig. 3: Female Panx3 KO mice weigh less than WT mice with no significant differences in body fat or lean mass.
Fig. 4: Female Panx3 KO mice have higher inflammatory index in quadriceps and liver tissues compared to WT mice.
Fig. 5: PANX3 expression is higher in male visceral fat tissue compared to females, and is regulated by FEX and dietary fat intake.
Fig. 6: Male Panx3 KO mice are protected from HFD induced inflammation compared to WT mice.
Fig. 7: Panx3 KO mice have fewer adipocytes and their primary adipose stromal cells (ASCs) grow slower than those isolated from WT mice.

Data availability

All data generated or analyzed during this study are included in the published article (and its online supplementary files). Raw data are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the funding agencies that supported this work including: Petro-Canada Young Innovator Award – Western University to SP, Ontario Graduate Scholarship to CBW. FB holds the Canada Research Chair in Musculoskeletal Research and is the recipient of a Foundation Grant from the Canadian Institutes of Health Research (CIHR, Grant #332438). CIHR Foundation Grant (FRN:FDN-143203) to AK. SP is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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CBW: project design, mouse husbandry, research data, data analysis, wrote manuscript; VRL: research data, data analysis, edited manuscript; DJ: research data, reviewed manuscript; PB: research data, data analysis; NJP: research data, data analysis, edited manuscript; SS, BLOD, JT, and RES-P: research data, data analysis, edited manuscript; KJB: research data, mouse husbandry, reviewed and edited manuscript; RG: research data, metabolic cage analysis; LF: research data, edited manuscript; NBM: research data, edited manuscript; AK: research data analysis, manuscript review and editing; FB: project design, manuscript review and editing, funding; SP: project design and supervision, data analysis, funding, manuscript review and editing.

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Correspondence to Silvia Penuela.

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Wakefield, C.B., Lee, V.R., Johnston, D. et al. Pannexin 3 deletion reduces fat accumulation and inflammation in a sex-specific manner. Int J Obes 46, 726–738 (2022). https://doi.org/10.1038/s41366-021-01037-4

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