Journal Article

HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance

Major, Jennifer L., Bagchi, Rushita A., Matsuda, Jennifer L., Robinson, Emma L., Bergman, Bryan C., McKinsey, Timothy A.

2023

Overview

Stimulation of adipocyte β-adrenergic receptors (β-ARs) induces expression of uncoupling protein 1 (UCP1), promoting nonshivering thermogenesis. Association of β-ARs with a lysine-myristoylated form of A kinase-anchoring protein 12 (AKAP12, also known as gravin-α) is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin-α by histone deacetylase 11 (HDAC11) suppresses this pathway. Whether inhibition of HDAC11 in adipocytes is sufficient to drive UCP1 expression independently of β-ARs is not known. Here, we demonstrate that adipocyte-specific deletion of HDAC11 in mice leads to robust induction of UCP1 in adipose tissue (AT), resulting in increased body temperature. These effects are mimicked by treating mice in vivo or human AT ex vivo with an HDAC11-selective inhibitor, FT895. FT895 triggers biphasic, gravin-α myristoylation-dependent induction of UCP1 protein expression, with a noncanonical acute response that is posttranscriptional and independent of protein kinase A (PKA), and a delayed response requiring PKA activity and new Ucp1 mRNA synthesis. Remarkably, HDAC11 inhibition promotes UCP1 expression even in models of adipocyte catecholamine resistance where β-AR signaling is blocked. These findings define cell-autonomous, multimodal roles for HDAC11 as a suppressor of thermogenesis, and highlight the potential of inhibiting HDAC11 to therapeutically alter AT phenotype independently of β-AR stimulation.

• Publisher: American Society for Clinical Investigation
• Subject: Adipocytes - drug effects / Adipocytes - metabolism / Adipose Tissue - metabolism / Adipose Tissue, Brown - metabolism / Adipose tissues / Animals / Catecholamine metabolism / Catecholamines - pharmacology / Cell receptors / Development and progression / Drug therapy / Enzyme inhibitors / Enzymes / Fat cells / Health aspects / Histone Deacetylase Inhibitors - pharmacology / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Humans / Hydrolases / Lysine / Medical research / Medicine, Experimental / Metabolism / Mice / Mirabegron / Obesity / Physiological aspects / Protein kinases / RNA / Thermogenesis / Thermogenesis - genetics / Uncoupling Protein 1 - genetics / Uncoupling Protein 1 - metabolism