KLF15 controls brown adipose tissue transcriptional flexibility and metabolism in response to various energetic demands

Liyan Fan; Alexander F Lesser; David R Sweet; Komal S Keerthy; Yuan Lu; Ernest R Chan; Vinesh Vinayachandran; Olga Ilkayeva; Tapatee Das; Christopher B Newgard; Mukesh K Jain

doi:10.1016/j.isci.2022.105292

KLF15 controls brown adipose tissue transcriptional flexibility and metabolism in response to various energetic demands

iScience. 2022 Oct 8;25(11):105292. doi: 10.1016/j.isci.2022.105292. eCollection 2022 Nov 18.

Authors

Liyan Fan^{1

2}, Alexander F Lesser^{1

2}, David R Sweet^{1

2}, Komal S Keerthy¹, Yuan Lu^{1

3}, Ernest R Chan⁴, Vinesh Vinayachandran¹, Olga Ilkayeva^{5

6}, Tapatee Das⁷, Christopher B Newgard^{5

6

8}, Mukesh K Jain⁷

Affiliations

¹ Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA.
² Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
³ Charles River Laboratories, Ashland, OH 44805, USA.
⁴ Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
⁵ Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
⁶ Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
⁷ Division of Biology and Medicine, Warren Alpert Medical School of Brown University, Providence, IR 02903, USA.
⁸ Department of Medicine and Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Abstract

Brown adipose tissue (BAT) is a specialized metabolic organ responsible for non-shivering thermogenesis. Recently, its activity has been shown to be critical in systemic metabolic health through its utilization and consumption of macronutrients. In the face of energetically demanding states, metabolic flexibility and systemic coordination of nutrient partitioning is requisite for health and survival. In this study, we elucidate BAT's differential transcriptional adaptations in response to multiple nutrient challenges and demonstrate its context-dependent prioritization of lipid, glucose, and amino acid metabolism. We show that the transcription factor Krüppel-like factor 15 (KLF15) plays a critical role in BAT metabolic flexibility. BAT-specific loss of KLF15 results in widespread changes in circulating metabolites and severely compromised thermogenesis in response to high energy demands, indicative of impaired nutrient utilization and metabolic flexibility. Together, our data demonstrate KLF15 in BAT plays an indispensable role in partitioning resources to maintain homeostasis and ensure survival.

Keywords: Cell biology; Human metabolism; Molecular biology.

Abstract

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