GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy
GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mecha...
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2017-08-01
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doaj-1d5d6bb81f4b48f7aa3c095bb5ab4e882021-05-03T10:24:41ZengElsevierJournal of Lipid Research0022-22752017-08-0158815611578GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacySanthosh Satapati0Ying Qian1Margaret S. Wu2Aleksandr Petrov3Ge Dai4Sheng-ping Wang5Yonghua Zhu6Xiaolan Shen7Eric S. Muise8Ying Chen9Emanuel Zycband10Adam Weinglass11Jerry Di Salvo12John S. Debenham13Jason M. Cox14Ping Lan15Vinit Shah16Stephen F. Previs17Mark Erion18David E. Kelley19Liangsu Wang20Andrew D. Howard21Jin Shang22Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., Kenilworth, NJ 07033Genetics and Pharmacogenomics, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Genetics and Pharmacology, Merck & Co., Inc., Kenilworth, NJ 07033Genetics and Pharmacology, Merck & Co., Inc., Kenilworth, NJ 07033Genetics and Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033Genetics and Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033Genetics and Chemistry, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033To whom correspondence should be addressed.; Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mechanism of action is not fully understood. Here, we postulated that the antidiabetic efficacy of GPR40 could be enhanced by coactivating GPR120. A combination of GPR40 and GPR120 agonists in db/db mice, as well as a single molecule with dual agonist activities, achieved superior glycemic control compared with either monotherapy. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in ob/ob mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Novel insights into the mechanism of action for GPR120 were obtained. Selective GPR120 activation suppressed lipolysis in primary white adipocytes, although this effect was attenuated in adipocytes from obese rats and obese rhesus, and sensitized the antilipolytic effect of insulin in rat and rhesus primary adipocytes. In conclusion, GPR120 agonism enhances insulin action in adipose tissue and yields a synergistic efficacy when combined with GPR40 agonism.http://www.sciencedirect.com/science/article/pii/S0022227520337834lipolysis and fatty acid metabolisminsulin resistancediabetesfatty acid |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Santhosh Satapati Ying Qian Margaret S. Wu Aleksandr Petrov Ge Dai Sheng-ping Wang Yonghua Zhu Xiaolan Shen Eric S. Muise Ying Chen Emanuel Zycband Adam Weinglass Jerry Di Salvo John S. Debenham Jason M. Cox Ping Lan Vinit Shah Stephen F. Previs Mark Erion David E. Kelley Liangsu Wang Andrew D. Howard Jin Shang |
spellingShingle |
Santhosh Satapati Ying Qian Margaret S. Wu Aleksandr Petrov Ge Dai Sheng-ping Wang Yonghua Zhu Xiaolan Shen Eric S. Muise Ying Chen Emanuel Zycband Adam Weinglass Jerry Di Salvo John S. Debenham Jason M. Cox Ping Lan Vinit Shah Stephen F. Previs Mark Erion David E. Kelley Liangsu Wang Andrew D. Howard Jin Shang GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy Journal of Lipid Research lipolysis and fatty acid metabolism insulin resistance diabetes fatty acid |
author_facet |
Santhosh Satapati Ying Qian Margaret S. Wu Aleksandr Petrov Ge Dai Sheng-ping Wang Yonghua Zhu Xiaolan Shen Eric S. Muise Ying Chen Emanuel Zycband Adam Weinglass Jerry Di Salvo John S. Debenham Jason M. Cox Ping Lan Vinit Shah Stephen F. Previs Mark Erion David E. Kelley Liangsu Wang Andrew D. Howard Jin Shang |
author_sort |
Santhosh Satapati |
title |
GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy |
title_short |
GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy |
title_full |
GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy |
title_fullStr |
GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy |
title_full_unstemmed |
GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy |
title_sort |
gpr120 suppresses adipose tissue lipolysis and synergizes with gpr40 in antidiabetic efficacy |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2017-08-01 |
description |
GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mechanism of action is not fully understood. Here, we postulated that the antidiabetic efficacy of GPR40 could be enhanced by coactivating GPR120. A combination of GPR40 and GPR120 agonists in db/db mice, as well as a single molecule with dual agonist activities, achieved superior glycemic control compared with either monotherapy. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in ob/ob mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Novel insights into the mechanism of action for GPR120 were obtained. Selective GPR120 activation suppressed lipolysis in primary white adipocytes, although this effect was attenuated in adipocytes from obese rats and obese rhesus, and sensitized the antilipolytic effect of insulin in rat and rhesus primary adipocytes. In conclusion, GPR120 agonism enhances insulin action in adipose tissue and yields a synergistic efficacy when combined with GPR40 agonism. |
topic |
lipolysis and fatty acid metabolism insulin resistance diabetes fatty acid |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520337834 |
work_keys_str_mv |
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