Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes

Ji Seul Han, Yong Geun Jeon, Minsik Oh, Gung Lee, Hahn Nahmgoong, Sang Mun Han, Jeehye Choi, Ye Young Kim, Kyung Cheul Shin, Jiwon Kim, Kyuri Jo, Sung Sik Choe, Eun Jung Park, Sun Kim and Jae Bum Kim ()
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Ji Seul Han: Seoul National University
Yong Geun Jeon: Seoul National University
Minsik Oh: Myongji University
Gung Lee: Seoul National University
Hahn Nahmgoong: Seoul National University
Sang Mun Han: Seoul National University
Jeehye Choi: Seoul National University
Ye Young Kim: Seoul National University
Kyung Cheul Shin: Seoul National University
Jiwon Kim: Seoul National University
Kyuri Jo: Chungbuk National University
Sung Sik Choe: Seoul National University
Eun Jung Park: National Cancer Center
Sun Kim: Seoul National University
Jae Bum Kim: Seoul National University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Thermogenic adipocytes generate heat to maintain body temperature against hypothermia in response to cold. Although tight regulation of thermogenesis is required to prevent energy sources depletion, the molecular details that tune thermogenesis are not thoroughly understood. Here, we demonstrate that adipocyte hypoxia-inducible factor α (HIFα) plays a key role in calibrating thermogenic function upon cold and re-warming. In beige adipocytes, HIFα attenuates protein kinase A (PKA) activity, leading to suppression of thermogenic activity. Mechanistically, HIF2α suppresses PKA activity by inducing miR-3085-3p expression to downregulate PKA catalytic subunit α (PKA Cα). Ablation of adipocyte HIF2α stimulates retention of beige adipocytes, accompanied by increased PKA Cα during re-warming after cold stimuli. Moreover, administration of miR-3085-3p promotes beige-to-white transition via downregulation of PKA Cα and mitochondrial abundance in adipocyte HIF2α deficient mice. Collectively, these findings suggest that HIF2α-dependent PKA regulation plays an important role as a thermostat through dynamic remodeling of beige adipocytes.

Date: 2022
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DOI: 10.1038/s41467-022-30925-0

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