Salazar, Mario G, Cervera, Iris P, French, Karen, Garcia-Martin, Ruben, Bluher, Matthias, Schofield, Chris, Chavakis, Trian, Gudmundsson, Elias F, Radcliffe, Peter, Jennings, Lori, Gudnason, Vilmundur, Morton, Nicholas M, Emilsson, Valur and Machailidou, Zoi (2022) Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality. https://www.biorxiv.org/content/10.1101/2021.01.05.425401v1.full.

Abstract

Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeutic strategy. A major obstacle to this strategy is that a thermoneutral environment, relevant to most modern human living conditions, deactivates functional BAT. We showed that we can overcome the dormancy of BAT at thermoneutrality by inhibiting the main oxygen sensor HIF-prolyl hydroxylase, PHD2, specifically in adipocytes. Mice lacking adipocyte PHD2 (P2KOad) and housed at thermoneutrality maintained greater BAT mass, UCP1 protein expression and higher energy expenditure. PHD2-deficiency facilitated higher sensitivity to b3-adrenergic stimulation. The elevated energy expenditure of P2KOadmice was sustained after a high-fat-feeding challenge at thermoneutrality. Mouse brown adipocytes treated with a pan-PHD inhibitor (PHDi), exhibited higher Ucp1mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, Hypoxia-inducible factor (HIF)-2a. Induction of UCP1mRNA expression by PHDi, was also confirmed in human adipocytes isolated from obese individuals. Human serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study revealed that serum PHD2 (aka EGLN1) associates with increased risk of metabolic disease. Our data suggest adipose–selective PHD2 inhibition as a novel therapeutic strategy for metabolic disease and identify serum PHD2 as a potential biomarker.

Item Type:	Article
Keywords:	Oxygen sensor; PHD2; adipocytes; BAT; thermoneutrality
Date Deposited:	21 Sep 2022 00:45
Last Modified:	21 Sep 2022 00:45
URI:	https://oak.novartis.com/id/eprint/47216