Adipocyte Ceramides Regulate Subcutaneous Adipose Browning, Inflammation, and Metabolism

Cell Metab. 2016 Dec 13;24(6):820-834. doi: 10.1016/j.cmet.2016.10.002.

Bhagirath Chaurasia ¹, Vincent Andre Kaddai ², Graeme Iain Lancaster ², Darren C Henstridge ³, Sandhya Sriram ⁴, Dwight Lark Anolin Galam ⁵, Venkatesh Gopalan ⁶, K N Bhanu Prakash ⁶, S Sendhil Velan ⁶, Sarada Bulchand ⁷, Teh Jing Tsong ⁸, Mei Wang ⁸, Monowarul Mobin Siddique ⁹, Guan Yuguang ⁵, Kristmundur Sigmundsson ⁵, Natalie A Mellet ¹⁰, Jacquelyn M Weir ¹⁰, Peter J Meikle ¹⁰, M Shabeer Bin M Yassin ¹¹, Asim Shabbir ¹², James A Shayman ¹³, Yoshio Hirabayashi ¹⁴, Sue-Anne Toh Ee Shiow ¹¹, Shigeki Sugii ¹⁵, Scott A Summers ²

Affiliations

1 Laboratory of Translational Metabolic Health, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia. Electronic address: [email protected].
2 Laboratory of Translational Metabolic Health, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
3 Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
4 Fat Metabolism and Stem Cell Group, Singapore Bioimaging Consortium, Singapore 138667, Singapore.
5 Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore 169547, Singapore.
6 Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Singapore 138667, Singapore.
7 Tata Institute of Fundamental Research, Navy Nagar, Mumbai 400005, India.
8 Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
9 Faculty of Science, University of Brunei Darussalam, Gadong 1410, Brunei Darussalam.
10 Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
11 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
12 Department of Surgery, National University of Singapore, Singapore 117599, Singapore.
13 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
14 RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
15 Fat Metabolism and Stem Cell Group, Singapore Bioimaging Consortium, Singapore 138667, Singapore; Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore 169547, Singapore.

PMID: 27818258 DOI: 10.1016/j.cmet.2016.10.002

Abstract

Adipocytes package incoming fatty acids into triglycerides and Other glycerolipids, with only a fraction spilling into a parallel biosynthetic pathway that produces sphingolipids. Herein, we demonstrate that subcutaneous adipose tissue of type 2 diabetics contains considerably more sphingolipids than non-diabetic, BMI-matched counterparts. Whole-body and adipose tissue-specific inhibition/deletion of serine palmitoyltransferase (Sptlc), the first enzyme in the sphingolipid biosynthesis cascade, in mice markedly altered adipose morphology and metabolism, particularly in subcutaneous adipose tissue. The reduction in adipose sphingolipids increased brown and beige/brite adipocyte numbers, mitochondrial activity, and Insulin sensitivity. The manipulation also increased numbers of anti-inflammatory M2 macrophages in the adipose bed and induced secretion of insulin-sensitizing adipokines. By comparison, deletion of serine palmitoyltransferase from macrophages had no discernible effects on metabolic homeostasis or adipose function. These data indicate that newly synthesized adipocyte sphingolipids are nutrient signals that drive changes in the adipose phenotype to influence whole-body energy expenditure and nutrient metabolism.

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