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 obesity-associated 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.

It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the DNA demethylase TET1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. TET1 acts as an autonomous repressor of key thermogenic genes, including Ucp1 and Ppargc1a, in beige adipocytes. Adipose-selective Tet1 knockout mice generated by using Fabp4-Cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. Moreover, the suppressive role of TET1 in the thermogenic gene regulation of beige adipocytes is largely DNA demethylase-independent. Rather, TET1 coordinates with HDAC1 to mediate the epigenetic changes to suppress thermogenic gene transcription. Taken together, TET1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. Our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.

The recognition of β cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain β cell identity. LIM domain-binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic β cells. Inducible ablation of LDB1 in mature β cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted β cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of β cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin-negative β cells express NEUROG3 but do not adopt alternate endocrine cell fates. In primary mouse islets, LDB1 and its LIM homeodomain-binding partner islet 1 (ISL1) were coenriched at chromatin sites occupied by pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), forkhead box A2 (FOXA2), and NK2 homeobox 2 (NKX2.2) - factors that co-occupy active enhancers in 3D chromatin domains in human islets. Indeed, LDB1 was enriched at active enhancers in human islets. Thus, LDB1 maintains the terminally differentiated state of β cells and is a component of active enhancers in both murine and human islets.