Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism.

Esther Paulo,Youngho Seo,Margaret Soucheray,Erica Stevenson,David Jimenez-Morales,Ruchi Masand,Danielle L Swaney,Tony L Huynh,Yun Zhang,Nevan J Krogan,Biao Wang

doi:10.1016/j.celrep.2021.109742

Esther Paulo, Youngho Seo + Show 9 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109742

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Abstract

Cold-induced thermogenesis in endotherms demands adaptive thermogenesis fueled by mitochondrial respiration and Ucp1-mediated uncoupling in multilocular brown adipocytes (BAs). However, dietary regulation of thermogenesis in BAs isn't fully understood. Here, we describe that the deficiency of Leucine-rich pentatricopeptide repeat containing-protein (Lrpprc) in BAs reduces mtDNA-encoded ETC gene expression, causes ETC proteome imbalance, and abolishes the mitochondria-fueled thermogenesis. BA-specific Lrpprc knockout mice are cold resistant in a 4°C cold-tolerance test in the presence of food, which is accompanied by the activation of transcription factor 4 (ATF4) and proteome turnover in BAs. ATF4 activation genetically by BA-specific ATF4 overexpression or physiologically by a low-protein diet feeding can improve cold tolerance in wild-type and Ucp1 knockout mice. Furthermore, ATF4 activation in BAs improves systemic metabolism in obesogenic environment regardless of Ucp1's action. Therefore, our study reveals a diet-dependent but Ucp1-independent thermogenic mechanism in BAs that is relevant to systemic thermoregulation and energy homeostasis.

Highlights

The adaptive thermogenesis refers to the heat production in response to changes in ambient temperature and diet, which mainly occurs in brown adipose tissue (BAT) containing multilocular and uncoupling protein 1 (Ucp1)+ brown adipocytes (BAs) (Cannon and Nedergaard, 2004, 2011)
We further demonstrate that disrupting the synchronization of mtDNA- and nuclear-encoded electron transport chain (ETC) protein expression induces diet- and activation of transcription factor 4 (ATF4)-dependent protein turnover in BAs, representing a Ucp1-independent thermogenic program in response to dietary changes
Leucine-rich pentatricopeptide repeat containing-protein (Lrpprc) expressed at a higher level in interscapular BAT than inguinal WAT and epididymal WAT (Figures S1A and S1B)

Summary

Introduction

The adaptive thermogenesis refers to the heat production in response to changes in ambient temperature and diet, which mainly occurs in brown adipose tissue (BAT) containing multilocular and Ucp1+ brown adipocytes (BAs) (Cannon and Nedergaard, 2004, 2011). We further demonstrate that disrupting the synchronization of mtDNA- and nuclear-encoded ETC protein expression induces diet- and ATF4-dependent protein turnover in BAs, representing a Ucp1-independent thermogenic program in response to dietary changes. This ATF4 activation in BAs can contribute to thermoregulation and promote metabolic health in obesogenic environment. Our observations suggest a new role of BAs in thermoregulation and energy metabolism

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Discussion

Conclusion