Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages

Yun Bu; Katsuhide Okunishi; Satomi Yogosawa; Kouichi Mizuno; Maria Johnson Irudayam; Chester W Brown; Tetsuro Izumi

doi:10.2337/db17-1201

Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages

Diabetes. 2018 Sep;67(9):1761-1772. doi: 10.2337/db17-1201. Epub 2018 Jun 26.

Authors

Yun Bu¹, Katsuhide Okunishi², Satomi Yogosawa¹, Kouichi Mizuno¹, Maria Johnson Irudayam³, Chester W Brown³, Tetsuro Izumi^{2

4}

Affiliations

¹ Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
² Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan tizumi@gunma-u.ac.jp okunishik@gunma-u.ac.jp.
³ Division of Genetics, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN.
⁴ Research Program for Signal Transduction, Division of Endocrinology, Metabolism and Signal Research, Gunma University Initiative for Advanced Research, Gunma University, Maebashi, Japan.

PMID: 29945891
DOI: 10.2337/db17-1201

Abstract

Previous genetic studies in mice have shown that functional loss of activin receptor-like kinase 7 (ALK7), a type I transforming growth factor-β receptor, increases lipolysis to resist fat accumulation in adipocytes. Although growth/differentiation factor 3 (GDF3) has been suggested to function as a ligand of ALK7 under nutrient-excess conditions, it is unknown how GDF3 production is regulated. Here, we show that a physiologically low level of insulin converts CD11c^- adipose tissue macrophages (ATMs) into GDF3-producing CD11c⁺ macrophages ex vivo and directs ALK7-dependent accumulation of fat in vivo. Depletion of ATMs by clodronate upregulates adipose lipases and reduces fat mass in ALK7-intact obese mice, but not in their ALK7-deficient counterparts. Furthermore, depletion of ATMs or transplantation of GDF3-deficient bone marrow negates the in vivo effects of insulin on both lipolysis and fat accumulation in ALK7-intact mice. The GDF3-ALK7 axis between ATMs and adipocytes represents a previously unrecognized mechanism by which insulin regulates both fat metabolism and mass.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activin Receptors, Type I / genetics
Activin Receptors, Type I / metabolism*
Adipose Tissue, White / drug effects*
Adipose Tissue, White / immunology
Adipose Tissue, White / metabolism
Adipose Tissue, White / pathology
Adiposity / drug effects
Animals
Bone Marrow Transplantation
CD11c Antigen / metabolism
Diet, High-Fat / adverse effects
Gene Expression Regulation / drug effects
Genes, Reporter / drug effects
Growth Differentiation Factor 3 / agonists*
Growth Differentiation Factor 3 / genetics
Growth Differentiation Factor 3 / metabolism
HEK293 Cells
Humans
Hypoglycemic Agents / pharmacology*
Hypoglycemic Agents / therapeutic use
Immunosuppressive Agents / pharmacology
Immunosuppressive Agents / therapeutic use
Insulin / pharmacology*
Insulin / therapeutic use
Lipolysis / drug effects*
Macrophages / drug effects*
Macrophages / immunology
Macrophages / metabolism
Macrophages / pathology
Male
Mice, Congenic
Mice, Inbred Strains
Mice, Knockout
Obesity / immunology
Obesity / metabolism
Obesity / pathology
Obesity / therapy
Weight Gain / drug effects

Substances

CD11c Antigen
Gdf3 protein, mouse
Growth Differentiation Factor 3
Hypoglycemic Agents
Immunosuppressive Agents
Insulin
Activin Receptors, Type I
Acvr1c protein, mouse