GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy

Satapati, Santhosh; Qian, Ying; Wu, Margaret; Petrov, A. N.; Dai, Ge; Wang, Shengping; Zhu, Y.; Shen, Xiaolan; Muise, Eric S.; Chen, Ying; Zycband, Emanuel; Weinglass, Adam B.; Salvo, Jerry Di; Debenham, John S.; Cox, Jason M.; Lan, Ping; Shah, Vinit; Previs, Stephen F.; Erion, Mark D.; Kelley, David E.; Wang, Liangsu; Howard, Andrew D.; Shang, Jin

doi:10.1194/jlr.m075044

Cited by 38 publications

(29 citation statements)

References 41 publications

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“…FA binding to GPR40 on pancreatic β-cells leads to activation of several signaling pathways involved in insulin secretion and targeting this receptor has shown to be a promising new treatment for T2DM, however safety concerns (hepatotoxicity) associated with current lead compounds have precluded their clinical use 6 . Recently, a dual GPR40 and GPR120 agonist showed potent activity on both adipose tissue lipolysis and glucose metabolism, highlighting the strong potential of these receptors in FA and glucose metabolism 7 .…”

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confidence: 99%

Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease

Simard

Thibodeau

Leduc

et al. 2020

Sci Rep

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Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. Although G protein-coupled receptor 84 (GPR84) has been associated with inflammation, its role in metabolic regulation remains elusive. The aim of our study was to evaluate the potential of PBI-4547 for the treatment of NAFLD and to validate the role of its main target receptor, GPR84. We report that PBI-4547 is a fatty acid mimetic, acting concomitantly as a GPR84 antagonist and GPR40/GPR120 agonist. In a mouse model of diet-induced obesity, PBI-4547 treatment improved metabolic dysregulation, reduced hepatic steatosis, ballooning and NAFLD score. PBI-4547 stimulated fatty acid oxidation and induced gene expression of mitochondrial uncoupling proteins in the liver. Liver metabolomics revealed that PBI-4547 improved metabolic dysregulation induced by a high-fat diet regimen. In Gpr84 −/− mice, PBI-4547 treatment failed to improve various key NAFLD-associated parameters, as was observed in wildtype littermates. Taken together, these results highlight a detrimental role for the GPR84 receptor in the context of meta-inflammation and suggest that GPR84 antagonism via PBI-4547 may reflect a novel treatment approach for NAFLD and its related complications. Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent chronic liver disease worldwide and is among the top three causes of liver transplantation in the US. NAFLD represents the pathological hepatic manifestation of metabolic dysregulation including fatty acid (FA) metabolism, not caused by excessive alcohol consumption, pro-steatogenic drugs or hereditary disorders and is defined by the presence of steatosis in the liver, due to triglyceride accumulation in hepatocytes (> 5% of total fat content) 1. Pathological signs range from steatosis to non-alcoholic steatohepatitis (NASH), which represents the most severe condition. Although the precise molecular mechanisms underlying the progression from simple steatosis to NASH remain elusive, several key risk factors are known to be intimately involved including inflammation, diet and infectious agents. The most important risk factor for NAFLD/NASH is type-II diabetes mellitus and remains a strong predictor for development of adverse clinical outcomes including advanced liver fibrosis and death. Other aggravating factors, such

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confidence: 99%

Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease

Simard

Thibodeau

Leduc

et al. 2020

Sci Rep

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“…Activation of GPR120 induces release of Fgf21 in BAT 35 . Interestingly, it has been shown that GPR120 suppresses adipose tissue lipolysis 36 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial 2,4-dienoyl-CoA reductase (Decr) deficiency and impairment of thermogenesis in mouse brown adipose tissue

Mäkelä

Hohtola

Miinalainen

et al. 2019

Sci Rep

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A large number of studies have demonstrated significance of polyunsaturated fatty acids (PUFAs) for human health. However, many aspects on signals translating PUFA-sensing into body homeostasis have remained enigmatic. To shed light on PUFA physiology, we have generated a mouse line defective in mitochondrial dienoyl-CoA reductase (Decr), which is a key enzyme required for β-oxidation of PUFAs. Previously, we have shown that these mice, whose oxidation of saturated fatty acid is intact but break-down of unsaturated fatty acids is blunted, develop severe hypoglycemia during metabolic stresses and fatal hypothermia upon acute cold challenge. In the current work, indirect calorimetry and thermography suggested that cold intolerance of Decr −/− mice is due to failure in maintaining appropriate heat production at least partly due to failure of brown adipose tissue (BAT) thermogenesis. Magnetic resonance imaging, electron microscopy, mass spectrometry and biochemical analysis showed attenuation in activation of lipolysis despite of functional NE-signaling and inappropriate expression of genes contributing to thermogenesis in iBAT when the Decr −/− mice were exposed to cold. We hypothesize that the failure in turning on BAT thermogenesis occurs due to accumulation of unsaturated long-chain fatty acids or their metabolites in Decr −/− mice BAT suppressing down-stream propagation of NE-signaling.

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“…Much effort has been put into the generation of FFA4 receptor agonists, however, it appears that none have yet reached clinical testing. An interesting concept has been advanced from demonstrations that simultaneous activation of FFA1 and FFA4 receptors has synergistic anti‐diabetic effects in animal models by virtue of dual glucose‐lowering and insulin‐sensitizing effects (Oh et al ., ; Satapati et al ., ). It has been proposed that a dual FFA1/FFA4 receptor agonist could be a highly efficacious anti‐diabetic agent as it is acting on several key tissues (i.e.…”

Section: Exploring Gpcr‐based Mechanisms To Increase Circulating Glp‐1mentioning

confidence: 97%

The current state of GPCR‐based drug discovery to treat metabolic disease

Sloop

Emmerson

Statnick

et al. 2018

British J Pharmacology

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GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy

Cited by 38 publications

References 41 publications

Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease

Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease

Mitochondrial 2,4-dienoyl-CoA reductase (Decr) deficiency and impairment of thermogenesis in mouse brown adipose tissue

The current state of GPCR‐based drug discovery to treat metabolic disease

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