Dual Role of Caspase 8 in Adipocyte Apoptosis and Metabolic Inflammation.

Abstract

Caspases are cysteine-aspartic proteases that were initially discovered to play a role in apoptosis. However, caspase 8, in particular, also has additional nonapoptotic 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 nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling. 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 noncanonical 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.

ARTICLE HIGHLIGHTS:

Caspase 8 is increased in adipocytes from mice and humans with obesity and insulin resistance. Knockdown of caspase 8 in adipocytes protects mice from glucose intolerance and weight gain on a high-fat diet. Knockdown of caspase 8 decreases Fas signaling, as well as canonical and noncanonical nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling in adipose tissue. Improved glucose tolerance occurs via reduced activation of NF-κB signaling and via induction of UCP1 in adipocytes.

• Authors: Cynthia T Luk, Carmen K Chan, Felix Chiu, Sally Yu Shi, Paraish S Misra, Yu Zhe Li, Evan Pollock-Tahiri, Stephanie A Schroer, Harsh R Desai, Tharini Sivasubramaniyam, Erica P Cai, Mansa Krishnamurthy, Daniel J Han, Apu Chowdhury, Rukhsana Aslam, Darren A Yuen, Anne Hakem, Razqallah Hakem, Minna Woo
• Journal: Diabetes (Diabetes) Vol. 72 Issue 12 Pg. 1751-1765 (Dec 01 2023) ISSN: 1939-327X [Electronic] United States
• PMID: 37699387 (Publication Type: Journal Article)
• Copyright: © 2023 by the American Diabetes Association.

Chemical References

• NF-kappa B
• Caspase 8
• Glucose

Topics

• Humans
• Male
• Female
• Animals
• Mice
• NF-kappa B (metabolism)
• Insulin Resistance (genetics)
• Caspase 8 (genetics, metabolism)
• Diabetes Mellitus, Type 2 (metabolism)
• Mice, Knockout
• Adipocytes (metabolism)
• Obesity (genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Inflammation (metabolism)
• Glucose (metabolism)
• Apoptosis (genetics)