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Cell Metab. 2019 Jul 2;30(1):174-189.e5. doi: 10.1016/j.cmet.2019.05.005. Epub 2019 May 30.

A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate.

Author information

1
Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
2
Department of Cancer Biology, University of Pennsylvania Philadelphia, PA, USA; AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, USA.
3
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
4
Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ, 08544 USA.
5
Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, Philadelphia, PA, USA; Genetics Department, University of Pennsylvania, Philadelphia, PA, USA.
6
Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA.
7
AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, USA.
8
Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, Philadelphia, PA, USA; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
9
Laboratory of Metabolic Control, NIH/NIAAA, Rockville, MD, USA.
10
Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: sealep@pennmedicine.upenn.edu.

Abstract

The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or β3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16-expressing adipose cells secreted the metabolite β-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.

KEYWORDS:

BDH1; PRDM16; UCP1; adipose fibrosis; beige fat; beta hydroxybutyrate; brown fat; fibro-adipogenic progenitor

PMID:
31155495
DOI:
10.1016/j.cmet.2019.05.005

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