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Synergistic activation of thermogenic adipocytes by a combination of PPARγ activation, SMAD3 inhibition and adrenergic receptor activation ameliorates metabolic abnormalities in rodents

Abstract

Aims/hypothesis

To treat obesity and related diseases, considerable effort has gone into developing strategies to convert white adipocytes into thermogenic brown-like adipocytes (‘browning’). The purpose of this study was to identify the most efficient signal control for browning.

Methods

To identify the most efficient signal control for browning, we examined rat stromal vascular fraction cells. In addition, physiological changes consequent to signal control were examined in vivo using lean and diet-induced obese (DIO) C57BL/6J mice.

Results

Combined treatment with the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone, the SMAD3 inhibitor SIS3 and the adrenergic receptor agonist noradrenaline (norepinephrine) synergistically induced Ucp1, Fgf21 and Cited1 expression, triggering brown adipogenesis. Synergistic induction of Ucp1 by the three agents was negatively regulated by forkhead box O (FOXO)3 via the inhibition of PPARγ-dependent gene transcription. Moreover, the administration of rosiglitazone, SIS3 and the selective β3 adrenergic receptor agonist CL316,243 to DIO mice reduced the amount of body-fat deposits (body weight from day 0 to 14, 12.3% reduction), concomitant with morphological changes in white adipose tissue, an increase in mitochondrial biosynthesis and a marked induction of uncoupling protein 1 (UCP1). Furthermore, administration of the three agents significantly increased serum adiponectin levels (mean 65.56 μg/ml with the three agents vs 20.79 μg/ml in control mice, p < 0.05) and improved glucose and lipid tolerance.

Conclusions/interpretation

These results suggest that the combined regulation of PPARγ, SMAD and the adrenergic receptor signalling pathway synergistically induces brown adipogenesis and may serve as an effective strategy to treat obesity and related diseases, including type 2 diabetes.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BAT:

Brown adipose tissue

CtBP:

C-terminal-binding protein

DIO:

Diet-induced obese

FOXO:

Forkhead box O

iWAT:

Inguinal white adipose tissue

MYF 5 :

Myogenic factor 5

nTZDpa :

Non-thiazolidinedione partial agonist of peroxisome proliferator-activated receptor γ

PGC1α:

Peroxisome proliferator-activated receptor γ coactivator 1α

PPARγ:

Peroxisome proliferator-activated receptor γ

PRDM16:

PRD1-BF1-RIZ1 homologous domain containing 16

siRNA:

Small interfering RNA

SIS3:

Specific inhibitor of SMAD3

SVF:

Stromal vascular fraction

TZD:

Thiazolidinedione

UCP1:

Uncoupling protein 1

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Acknowledgements

We thank our colleagues in the Biological Science Laboratories, Kao Corporation, for the helpful discussions.

Funding

This work was supported financially by Kao Corporation. The study sponsor was not involved in the design of the study; the collection, analysis or interpretation of data; writing the report; or the decision to submit the report for publication.

Author information

TMu conceived and designed the research. TMa and SK performed experiments. TMu, SK and TMa wrote the manuscript and had final approval of the version to be published. TMu is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Correspondence to Takatoshi Murase.

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Matsumoto, T., Kiuchi, S. & Murase, T. Synergistic activation of thermogenic adipocytes by a combination of PPARγ activation, SMAD3 inhibition and adrenergic receptor activation ameliorates metabolic abnormalities in rodents. Diabetologia 62, 1915–1927 (2019). https://doi.org/10.1007/s00125-019-4938-6

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Keywords

  • Adipocytes
  • Browning
  • FOXO3
  • Obesity
  • PPARγ agonist