Phytochemicals as novel agents for the induction of browning in white adipose tissue

Yusra Azhar, Ashish Parmar, Colette N Miller, Janaiya S Samuels, Srujana Rayalam, Yusra Azhar, Ashish Parmar, Colette N Miller, Janaiya S Samuels, Srujana Rayalam

Abstract

Obesity and its associated metabolic syndrome continue to be a health epidemic in westernized societies and is catching up in the developing world. Despite such increases, little headway has been made to reverse adverse weight gain in the global population. Few medical options exist for the treatment of obesity which points to the necessity for exploration of anti-obesity therapies including pharmaceutical and nutraceutical compounds. Defects in brown adipose tissue, a major energy dissipating organ, has been identified in the obese and is hypothesized to contribute to the overall metabolic deficit observed in obesity. Not surprisingly, considerable attention has been placed on the discovery of methods to activate brown adipose tissue. A variety of plant-derived, natural compounds have shown promise to regulate brown adipose tissue activity and enhance the lipolytic and catabolic potential of white adipose tissue. Through activation of the sympathetic nervous system, thyroid hormone signaling, and transcriptional regulation of metabolism, natural compounds such as capsaicin and resveratrol may provide a relatively safe and effective option to upregulate energy expenditure. Through utilizing the energy dissipating potential of such nutraceutical compounds, the possibility exists to provide a therapeutic solution to correct the energy imbalance that underlines obesity.

Figures

Fig. 1
Fig. 1
Developmental origins of white, brown and beige adipocytes. Beige adipocytes are derived from mesenchymal stem cells (Myf5−) and are closely related to white adipocytes, while brown adipocytes are derived from Myf5+ precursor cells and are closely related to muscle lineage
Fig. 2
Fig. 2
Model for the induction of browning by phytochemicals. Guggulsterone binds to TGR5 and increases the expression of DIO2 which in turn enhances T3 levels leading to the induction of beiging. Resveratrol is a sirtuin activator and enhances the levels of cAMP and also activates AMPK. SIRT1 mediates PGC1α deacetylation and AMPK activates PGC1α. PRDM16 co-activates PGC1α and PPARγ driving the upregulation of thermogenic genes. Likewise, naringenin also activates SIRT1 contributing to the induction of beiging. Abbreviations: AMPK (5’ adenosine monophosphate activated protein kinase), DIO2 (type 2 deiodinase), PGC-1α (PPARγ coactivator 1α), PPARγ (peroxisome proliferator-activated receptor γ), PRDM16 (PR domain containing protein 16), SIRT1 (sirtuin 1) and T3 (tri-iodothyronine)
Fig. 3
Fig. 3
Possible TGR5-medaited effects of guggulsterone and xanthohumol. The structural similarity of guggulsterone and xanthohumol to bile acids allows them to bind to bile acid receptor TGR5 which induces cAMP mediated upregulation of DIO2. DIO2 converts T4 to biologically active T3, which in turn induces UCP1 and increases thermogenic activity of mitochondria. Abbreviations: cAMP (cyclic adenosine monophosphate), DIO2 (type 2 deiodinase), UCP1 (uncoupling protein 1)

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