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Dual role of caspase 8 in adipocyte apoptosis and metabolic inflammation

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posted on 2023-09-12, 22:24 authored by Cynthia T. Luk, Carmen K. Chan, Felix Chiu, Sally Yu Shi, Paraish Misra, Yu Zhe Li, Evan Pollock-Tahiri, Stephanie A. Schroer, Harsh R. Desai, Tara Sivasubramaniyam, Erica P. Cai, Mansa Krishnamurthy, Daniel J. Han, Apu Chowdhury, Rukhsana Aslam, Darren A. Yuen, Razqallah Hakem, Minna Woo

Caspases are cysteine-aspartic proteases that were initially discovered to play a role in apoptosis. However, caspase 8, in particular, also has additional non-apoptotic roles, such as in inflammation. Adipocyte cell death and inflammation are hypothesized to be initiating pathogenic factors in type 2 diabetes. Here, we examined the pleiotropic role of caspase 8 in adipocytes and obesity-associated insulin resistance. Caspase 8 expression was increased in adipocytes from mice and humans with obesity and insulin resistance. Treatment of 3T3-L1 adipocytes with caspase 8 inhibitor Z-IETD-FMK decreased both death receptor-mediated signaling and targets of NF-κBsignaling. We generated novel adipose tissue and adipocyte-specific caspase 8 knockout mice (aP2Casp8-/- and adipoqCasp8-/-). Both males and females had improved glucose tolerance in the setting of high fat diet (HFD) feeding. Knockout mice also gained less weight on HFD, with decreased adiposity, adipocyte size and hepatic steatosis. These mice had decreased adipose tissue inflammation and decreased activation of canonical and non-canonical NF-κB signaling. Furthermore, they demonstrated increased energy expenditure, core body temperature, and UCP1 expression. Adipocyte-specific activation of Ikbkb or housing mice at thermoneutrality attenuated improvements in glucose tolerance. These data demonstrate an important role for caspase 8 in mediating adipocyte cell death and inflammation to regulate glucose and energy homeostasis.

Funding

This work was supported by Canadian Institutes of Health Research (CIHR) Operating Grant MOP-93707 to MW. This work was also supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) discovery grant RGPIN-2018-05671, J.P. Bickell Foundation grant, Banting and Best Diabetes Centre (BBDC) New Investigator Award, Heart and Stroke Richard Lewar Centres of Excellence in Cardiovascular Research (HSRLCE) and BI-LILLY new investigator award, Canadian Institutes of Health Research (CIHR) project grant PJT-168996 and CIHR early career investigator award ARI-170743 to CTL. MW is supported by Canada Research Chair in Signal Transduction Diabetes Pathogenesis. CTL was supported by a Heart and Stroke Heart and Stroke Canada (HSFC) new investigator award. DJH was supported by a BBDC-Novo Nordisk graduate studentship and Ontario Graduate Scholarship (OGS). CKC is supported by a Keenan Research Centre for Biomedical Science Research Trainee Centre top-up award.

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