Adipocyte Ceramides Regulate Subcutaneous Adipose Browning, Inflammation, and Metabolism.
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.
Laboratory of Translational Metabolic Health, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia. Electronic address: bhagirath.chaurasia@health.utah.edu.
Bhagirath
B
Chaurasia
Laboratory of Translational Metabolic Health, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
Vincent Andre
VA
Kaddai
Laboratory of Translational Metabolic Health, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
Graeme Iain
GI
Lancaster
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
Darren C
DC
Henstridge
Fat Metabolism and Stem Cell Group, Singapore Bioimaging Consortium, Singapore 138667, Singapore.
Sandhya
S
Sriram
Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore 169547, Singapore.
Dwight Lark Anolin
DL
Galam
Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Singapore 138667, Singapore.
Venkatesh
V
Gopalan
Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Singapore 138667, Singapore.
K N Bhanu
KN
Prakash
Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Singapore 138667, Singapore.
S Sendhil
SS
Velan
Tata Institute of Fundamental Research, Navy Nagar, Mumbai 400005, India.
Sarada
S
Bulchand
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
Teh Jing
TJ
Tsong
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
Mei
M
Wang
Faculty of Science, University of Brunei Darussalam, Gadong 1410, Brunei Darussalam.
Monowarul Mobin
MM
Siddique
Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore 169547, Singapore.
Guan
G
Yuguang
Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore 169547, Singapore.
Kristmundur
K
Sigmundsson
Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
Natalie A
NA
Mellet
Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
Jacquelyn M
JM
Weir
Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
Peter J
PJ
Meikle
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
M Shabeer
MS
Bin M Yassin
Department of Surgery, National University of Singapore, Singapore 117599, Singapore.
Asim
A
Shabbir
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
James A
JA
Shayman
RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
Yoshio
Y
Hirabayashi
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
Sue-Anne Toh Ee
ST
Shiow
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.
Shigeki
S
Sugii
Laboratory of Translational Metabolic Health, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
Scott A
SA
Summers
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000818:Animals; D015992:Body Mass Index; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002518:Ceramides / Q000494:pharmacology*; D003080:Cold Temperature; D003920:Diabetes Mellitus / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D013107:Sphingolipids / Q000096:biosynthesis / Q000378:metabolism; D050151:Subcutaneous Fat / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D022722:Thermogenesis / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
D000318:Adrenergic beta-Agonists; D002518:Ceramides; D004149:Dioxoles; D013107:Sphingolipids; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D051102:Serine C-Palmitoyltransferase; C495090:Sptlc2 protein, mouse; D005947:Glucose