Novel Browning Agents, Mechanisms, and Therapeutic Potentials of Brown Adipose Tissue

Table 1

Several browning agents (genes, microRNAs, and pharmacological, chemical, or plant-based products) that induce browning/browning in adipose tissue and provide protection from HFD-induced obesity.

Browning agents	Effect on browning and metabolic outcome	Reference
Gain of function/overexpression
Ucp1	Less lipid accumulation in adipocytes, resistance to HFD-induced obesity, beige cell phenotype in WAT, atrophy of BAT, and reduced Ucp1 and mitochondrial DNA content in BAT	[38, 39]
Prdm16	Beige adipocyte induction in WAT when stimulated by b-AR, increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a HFD	[40]
Cox2	Ucp1 induction in WAT via stimulation of β-AR, increased thermogenesis, attenuated weight loss and energy expenditure, and protection against HFD-induced obesity	[44, 45]
LXA4	Higher LXA4 levels were related to browning of WAT, leaner body type, increased energy expenditure, and increased thermogenesis	[46, 47]
Foxc2	Increased b-AR-cAMP-PKA signaling was associated with reduced fat mass and browning of WAT and protection against HFD-induced obesity	[48]
Pten	BAT in Pten-overexpressing mice had high levels of Ucp1 and increased energy expenditure	[49]
AM2	Overexpression in adipose tissue led to reduced acetylation of Pgc1α and favorable interaction between Pgc1α, Prdm16, and Ucp1 in adipocytes, induction of browning in WAT, and protection against HFD-induced obesity	[52]
Loss of function/knockdown
BMP7	Absence of BMP7 led to reduced interscapular BAT at birth	[53, 54]
Smad3/Tgfb	Improved glucose homeostasis with induction of beige cells in WAT which provided protection against obesity and increased mitochondrial bioenergetic profile of WAT	[56]
ABHD6	Increased energy expenditure, cold-induced thermogenesis, Ucp1 expression in WAT, fatty acid oxidation, browning of WAT, protection against HFD-induced obesity, and associated complications	[58]
Ga	Activation of Gα signaling abrogates brown adipogenesis, whereas expression of Gα signaling is inversely correlated with Ucp1 expression in WAT
Folliculin	Mitochondrial uncoupling proteins as well as other markers of brown fat are upregulated in both white and brown FLCN-null adipose tissues	[51]
IEX-1	Induced browning of WAT, enhanced thermogenesis with markedly less weight gain, and increased energy expenditure on HFD	[59]
LXR	Induction of beige adipocytes in WAT of mice fed a normal diet with improved metabolic phenotype	[60]
MicroRNAs and browning
miR-455	Expressed in BAT-specific manner, induced by cold exposure, and induced browning in subcutaneous fat upon cold exposure	[64]
miR-92a	Inversely correlated with BAT activity in humans and could be used as a potential biomarker for BAT activity in mice and humans	[65]
Pharmacological and plant-based browning agents
CL 316243	β3AR agonist induces browning in WAT, strong response to cold in the form of increased thermogenesis, increased Ucp1 mRNA in WAT and BAT upon treatment, weight loss, and improved energy expenditure	[66–69]
Gleevec	Increased browning of WAT and rate of energy expenditure, acting by blocking PPARg phosphorylation	[70]
Acetate	Increased heat production from brown and beige adipocytes corroborated by increased Ucp1 and Prdm16 expression in WAT	[71]
TZDs	Transforming WAT into BAT-like tissue with increased angiogenesis	[72]
PGE2	Browning induction in WAT with improved angiogenesis	[72]
Slit2 derived secretory product	Acting via Prdm16 to regulate beige adipocyte induction, increasing Ucp1 expression, and promoting adipose thermogenesis resulting in increased energy expenditure	[61]
Butyrate	Increased expression of Ucp-1 and Pgc1α and protected high fat diet-induced obesity in mice	[73]
Rapamycin	βAR-dependent increase in Ucp1 expression and expansion of beige adipocyte in WAT	[62]
Plant-based browning agents
Butein	Ucp1 induction in WAT, mediated through Prdm4, leads to increased energy expenditure and stimulates generation of thermogenic adipocytes	[74]
Resveratrol	Reducing adipose tissue inflammation and increased expression of genes associated with the browning of adipose tissue	[75]
-Lapachone	Stimulating the browning of WAT, increased expression of BAT-specific genes, decreased body weight gain, and ameliorated HFD effects	[76]
Capsaicin	Acting via TRPV1 channel, increased the expression of Pgc1 and Prdm16 and induced browning in adipose tissue, and provided protection from HFD-induced obesity	[77]