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JMJD8 is a Novel Molecular Nexus Between Adipocyte-Intrinsic Inflammation and Insulin Resistance

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posted on 22.10.2021, 18:52 authored by Dongjoo You, Byung Chul Jung, Sneha Damal Villivalam, Hee-Woong Lim, Sona Kang
Chronic low-grade inflammation, often referred to as metainflammation, develops in response to overnutrition and is a major player in the regulation of insulin sensitivity. While many studies have investigated adipose tissue inflammation from the perspective of the immune cell compartment, little is known about how adipocytes intrinsically contribute to metainflammation and insulin resistance at the molecular level. Here, we demonstrate a novel role for Jumonji C Domain Containing Protein 8 (JMJD8) as an adipocyte-intrinsic molecular nexus between inflammation and insulin resistance. We determined that JMJD8 was highly enriched in white adipose tissue, especially in the adipocyte fraction. Adipose JMJD8 levels were dramatically increased in obesityassociated insulin resistance models. Its levels were increased by feeding and insulin, and inhibited by fasting. A JMJD8 gain-of-function was sufficient to drive insulin resistance, whereas loss-of-function improved insulin sensitivity in mouse and human adipocytes. Consistent with this, Jmjd8-ablated mice had increased whole-body and adipose insulin sensitivity and glucose tolerance on both chow and a high-fat diet, while adipocyte-specific Jmjd8-overexpressing mice displayed worsened whole-body metabolism on a high-fat diet. We found that JMJD8 affected the transcriptional regulation of inflammatory genes. In particular, it was required for LPS-mediated inflammation and insulin resistance in adipocytes. For this, JMJD8 required Interferon Regulatory Factor (IRF3) to mediate its actions in adipocytes. Together, our results demonstrate that JMJD8 acts as a novel molecular factor that drives adipocyte inflammation in conjunction with insulin sensitivity.

Funding

U.S. Department of Health and Human Services > National Institutes of Health > National Institute of Diabetes and Digestive and Kidney Diseases DK116008 Stanford Diabetes Research Center P30DK116074

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