Oncostatin M suppresses browning of white adipocytes via gp130-STAT3 signaling

Pim P van Krieken; Timothy S Odermatt; Marcela Borsigova; Matthias Blüher; Stephan Wueest; Daniel Konrad

doi:10.1016/j.molmet.2021.101341

Oncostatin M suppresses browning of white adipocytes via gp130-STAT3 signaling

Mol Metab. 2021 Dec:54:101341. doi: 10.1016/j.molmet.2021.101341. Epub 2021 Sep 20.

Authors

Pim P van Krieken¹, Timothy S Odermatt², Marcela Borsigova¹, Matthias Blüher³, Stephan Wueest¹, Daniel Konrad⁴

Affiliations

¹ Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, CH-8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital, University of Zurich, CH-8032, Zurich, Switzerland.
² Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, CH-8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital, University of Zurich, CH-8032, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, CH-8057, Zurich, Switzerland.
³ Department of Medicine, Endocrinology and Diabetes, University of Leipzig, D-04103, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Germany.
⁴ Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, CH-8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital, University of Zurich, CH-8032, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, CH-8057, Zurich, Switzerland. Electronic address: daniel.konrad@kispi.uzh.ch.

Abstract

Objective: Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state.

Methods: Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130^Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively.

Results: Inguinal WAT of HFD-fed gp130^Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = -0.413, p < 0.001, n = 66).

Conclusions: Our data support the notion that OSM negatively regulates thermogenesis in WAT and thus may be an attractive target for treating obesity.

Keywords: Browning; High-fat diet; Obesity; Oncostatin M; UCP1; White adipose tissue.

Publication types

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

MeSH terms

3T3-L1 Cells
Adipocytes, White / metabolism
Animals
Cells, Cultured
Cytokine Receptor gp130 / metabolism*
Humans
Male
Mice
Oncostatin M / genetics
Oncostatin M / metabolism*
STAT3 Transcription Factor / metabolism*

Substances

IL6ST protein, human
Il6st protein, mouse
OSM protein, human
Osm protein, mouse
STAT3 Transcription Factor
STAT3 protein, human
Stat3 protein, mouse
Oncostatin M
Cytokine Receptor gp130