RANKL induces beige adipocyte differentiation in preadipocytes

Apr 22, 2020American journal of physiology. Endocrinology and metabolism

RANKL helps immature fat cells develop into energy-burning beige fat cells

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Abstract

Osteoprotegerin knockout (OPG-/-) mice exhibited resistance to high-fat diet-induced weight gain and enhanced glucose metabolism.

Histological analysis revealed browning of subcutaneous white adipose tissue (sWAT) in OPG-/- mice.
Stromal vascular fraction cells from OPG-/- mice displayed multilocular morphology and higher expression of brown adipocyte marker genes.
RANKL infusion led to browning and increased respiratory rates in sWAT, along with elevated whole body oxygen consumption.
Subcutaneous WAT-derived stromal vascular fraction and 3T3-L1 cells differentiated into beige adipose tissue upon RANKL exposure.
RANKL stimulation resulted in multilocular lipid droplets and increased expression of beige adipocyte markers in developing adipocytes.

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The receptor activator of nuclear factor-κB (NF-κB) (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG) are a triad of proteins that regulate bone metabolism, and serum OPG is considered a biomarker for cardiovascular diseases and Type 2 diabetes; however, the implications of OPG in adipose tissue metabolism remains elusive. In this study, we investigate RANK-RANKL-OPG signaling in white adipose tissue browning. Histological analysis of osteoprotegerin knockout (OPG-/-) mice showed subcutaneous white adipose tissue (sWAT) browning, resistance for high-fat diet-induced weight gain, and preserved glucose metabolism compared with wild-type (WT) mice. Stromal vascular fraction (SVF) cells from sWAT of OPG-/- mice showed multilocular morphology and higher expression of brown adipocyte marker genes compared with those from the WT group. Infusion of RANKL induced browning and elevated respiratory rates in sWAT, along with increased whole body oxygen consumption in mice measured by indirect calorimetry. Subcutaneous WAT-derived SVF and 3T3-L1 cells, but not mature white adipocytes, differentiated into beige adipose tissue in the presence of RANKL. Moreover, SVF cells, even under white adipocyte differentiation, showed multilocular lipid droplet, lower lipid content, and increased expression of beige adipocyte markers with RANKL stimulation. In this study, we show for the first time the contribution of RANKL to increase energy expenditure by inducing beige adipocyte differentiation in preadipocytes.

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RANKL induces beige adipocyte differentiation in preadipocytes

Abstract

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