Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

GOMEZ SALAZAR, M.; PRUNONOSA CERVERA, I.; WANG, R.; FRENCH, K.; GARCIA-MARTIN, R.; BLÜHER, M.; SCHOFIELD, C. J.; STIMSON, R. H.; CHAVAKIS, T.; GUDMUNDSSON, E. F.; JENNINGS, L. L.; GUDNASON, V. G.; MORTON, N. M.; EMILSSON, V.; MICHAILIDOU, Z.

doi:10.1101/2021.01.05.425401

bioRxiv · 10.1101/2021.01.05.425401

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

GOMEZ SALAZAR, M.·PRUNONOSA CERVERA, I.·WANG, R.·FRENCH, K.·GARCIA-MARTIN, R.·BLÜHER, M.·SCHOFIELD, C. J.·STIMSON, R. H.·CHAVAKIS, T.·GUDMUNDSSON, E. F.·JENNINGS, L. L.·GUDNASON, V. G.·MORTON, N. M.·EMILSSON, V.·MICHAILIDOU, Z.

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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, had detectable UCP1 protein expression in BAT and higher energy expenditure. Mouse brown adipocytes treated with the pan-PHD inhibitor, FG2216, exhibited higher Ucp1 mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, HIF-2a. Induction of UCP1 mRNA expression by FG2216, 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.

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GOMEZ SALAZAR, M., PRUNONOSA CERVERA, I., WANG, R., FRENCH, K., GARCIA-MARTIN, R., BLÜHER, M., SCHOFIELD, C. J., STIMSON, R. H., CHAVAKIS, T., GUDMUNDSSON, E. F., JENNINGS, L. L., GUDNASON, V. G., MORTON, N. M., EMILSSON, V., MICHAILIDOU, Z.. 2021-01-06. Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality. https://doi.org/10.1101/2021.01.05.425401

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