HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

Abstract

Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cellbased assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to -adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. These findings define a novel epigenetic pathway for the regulation of energy homeostasis, and suggest potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.suggest the intriguing possibility that selective HDAC11 inhibitors could be developed to increase energy expenditure for the treatment of obesity and metabolic disease.

Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures

“…The genes associated with the DMR were functionally categorized and evaluated for gene pathway association utilizing the KEGG database, as described in the Methods. Several metabolic related pathways were identified, and literature searches of many of the genes revealed several genes associated with adipogenesis [63,64] adipocyte beiging/browning [65,66], insulin resistance [67][68][69], and lipolysis [70,71]. Changes in these functions in the adipocyte and adipocyte precursors may promote obesity and metabolic dysregulation [72].…”

The role of HDAC11 in obesity‐related metabolic disorders: A critical review

“…In addition, HDAC11 enzymatic activity seems to be necessary to inhibit adipocyte gene expression (Bagchi et al, 2018). This also germinated the use of HDAC11 selective small‐molecule inhibitors to increase energy expenditure to achieve the purpose of antiobesity.…”

“…HDAC11 is involved in regulating the process of regulating metabolism and obesity (Bhaskara, 2018; L. Sun et al, 2018). Researchers have studied the biological functions of HDAC11 and found that inhibiting HDAC11 could increase the body's energy consumption to treat obesity and metabolic diseases (Bagchi et al, 2018). The loss of HDAC11 promoted the ability to generate heat, increased energy consumption, and promoted uncoupling protein‐1 expression, thereby enabling the metabolic clearance store.…”

“…These changes were important because the role of white fat was to store excess energy in the body in the form of fat, forming obesity that people usually did not want to see, and brown fat could convert fat into calories (Sidossis & Kajimura, 2015). On the basis of study results, mice lacking the HDAC11 enzyme were often protected from the adverse effects of obesity, insulin resistance, and other high‐fat feedings (Bagchi et al, 2018). Not only that HDAC11‐knockout (KO) could suppress the occurrence of obesity induced by the high‐fat diet.…”

Characterization of Histone Deacetylase Mechanisms in Cancer Development

“…Similar to Sirtuins, HDAC11 also possesses acylase activity. Determination of defatty-acylase activity is considered an alternative method of identifying HDACs, and zinc-dependent HDACs showed notable differences in activity ( 67 , 68 ). HDAC11 participates in oligodendrocyte progression and promotes oligodendrocyte differentiation ( 69 ).…”