Elucidation of the role of a lysine demyristoylase in adipose tissue‐myocardium crosstalk in cardiometabolic disease

Histone deacetylase 11 (HDAC11) is the lone class IV HDAC whose biological function is largely unexplored. Previously, we demonstrated that deletion of HDAC11 in vivo stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT) via a genomic mechanism dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl‐histone binding protein in brown adipocytes. Here, we hypothesize that HDAC11 inactivation primes the heart for protection from pathological remodeling consequent to diet‐induced obesity (DIO) via modulation of adipose tissue transcriptome and secretome (Figure ). Gene expression analysis showed that selective pharmacologic inhibition of HDAC11 promotes brown adipocyte formation and Ucp1 expression in vitro and in vivo . HDAC11‐deficient mice, in response to high‐fat feeding, exhibit attenuated obesity, insulin resistance, and hepatic steatosis, concomitant with increased levels of the circulating cardioprotective hormone adiponectin. Using histological analysis, atomic force microscopy and quantitative mass spectrometry, we demonstrate that adipose tissue lacking HDAC11 is protected from pathologic remodeling as a consequence of chronic high caloric diet administration. At the level of the heart, we demonstrate for the very first time that HDAC11 functions as a negative regulator of physiological hypertrophy. HDAC11‐deficient hearts exhibit attenuated hypertrophic gene expression after chronic high‐fat feeding. HDAC11 loss also protects cardiomyocytes from pathological hypertrophy and fetal gene activation induced by high fat serum. Using orthogonal click chemistry, fluorescence correlation spectroscopy and super‐resolution microscopy, we establish for the first time that HDAC11 exerts its non‐genomic action by modifying fatty acylation of a cytosolic scaffolding protein, AKAP12 (a.k.a. gravin) and regulation of β‐adrenergic receptor signaling (Figure ). These findings outline a novel and highly druggable pathway for the regulation of cardiometabolic disease at the level of adipose tissue and the heart, and suggest a potential for HDAC11‐selective inhibitors for the treatment of obesity and cardiometabolic disease. Support or Funding Information This work was supported by NIH (HL116848, HL127240, HL147558, DK119594) and the American Heart Association (16SFRN31400013) to T.A.M. R.A.B. (FRN‐216927) and J.L.M. (FRN‐395620) received funding from the Canadian Institutes of Health Research. Proposed model for HDAC11‐mediated cross‐talk between adipose tissue and the heart in cardiometabolic disease. Figure 1 Schematic of the mechanism for HDAC11 modulation of AKAP12‐mediated βAR signaling. Figure 2

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