Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models

Guo, Danyang; Li, Dewen; Ning, Man; Dang, Xiangyu; Zhang, Lina; Zeng, Limin; Hu, Youhong; Liu, Ying

doi:10.1016/j.bbrc.2015.09.130

Cited by 14 publications

(7 citation statements)

References 23 publications

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“…palmitate induces a two-fold increase in GLP-1 secretion from untreated cells versus a four-fold increase in secretion from oleate pre-treated cells (Fig 3C). Thissecretory effect of palmitate is indicated, in accordance with what has previously been reported [29, 30], to be mediated by FFAR1 (Fig 3D). …”

Section: Resultssupporting

confidence: 93%

Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

et al. 2017

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Background and aimFatty acids acutely stimulate GLP-1 secretion from L-cells in vivo. However, a high fat diet has been shown to reduce the density of L-cells in the mouse intestine and a positive correlation has been indicated between L-cell number and GLP-1 secretion. Thus, the mechanism of fatty acid-stimulated GLP-1 secretion, potential effects of long-term exposure to elevated levels of different fatty acid species, and underlying mechanisms are not fully understood. In the present study, we sought to determine how long-term exposure to saturated (16:0) and unsaturated (18:1) fatty acids, by direct effects on GLP-1-producing cells, alter function and viability, and the underlying mechanisms.MethodsGLP-1-secreting GLUTag cells were cultured in the presence/absence of saturated (16:0) and unsaturated (18:1) fatty acids (0.125 mM for 48 h, followed by analyses of viability and apoptosis, as well as involvement of fatty acid oxidation, free fatty acid receptors (FFAR1) and ceramide synthesis. In addition, effects on the expression of proglucagon, prohormone convertase 1/3 (PC1/3), free fatty acid receptors (FFAR1, FFAR3), sodium glucose co-transporter (SGLT) and subsequent secretory response were determined.ResultsSaturated (16:0) and unsaturated (18:1) fatty acids exerted opposing effects on the induction of apoptosis (1.4-fold increase in DNA fragmentation by palmitate and a 0.5-fold reduction by oleate; p<0.01). Palmitate-induced apoptosis was associated with increased ceramide content and co-incubation with Fumonisin B1 abolished this lipo apoptosis. Oleate, on the other hand, reduced ceramide content, and—unlike palmitate—upregulated FFAR1 and FFAR3, evoking a 2-fold increase in FFAR1-mediated GLP-1 secretion following acute exposure to 0.125 mmol/L palmitate; (p<0.05).Conclusion/InterpretationSaturated (16:0), but not unsaturated (18:1), fatty acids induce ceramide-mediated apoptosis of GLP-1-producing cells. Further, unsaturated fatty acids confer lipoprotection, enhancing viability and function of GLP-1-secreting cells. These data provide potential mechanistic insight contributing to reduced L-cell mass following a high fat diet and differential effects of saturated and unsaturated fatty acids on GLP-1 secretion in vivo.

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Section: Resultssupporting

confidence: 93%

Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

et al. 2017

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“…Therefore, further screening and structural optimization, as well as longterm evaluation of effectiveness and safety, are required urgently to the development of full agonists. Notably, the agonists LY2881835, 20 BMS-986118, 167 Yhhu4488, 176 and MK-2305 29 also revealed a significant increase in plasma GLP-1 levels.…”

Section: A Are Ffar1 Full Agonists Better Than Partial Agonists?mentioning

confidence: 97%

“…Unlike TAK‐875, the representative compound Yhhu4488 ( 85 , hEC 50 = 49.96 nM) revealed a significantly enhanced GLP‐1 release in ob / ob mice. After 22 days of treatment in ob / ob mice, Yhhu4488 (100 mg/kg) showed dual effects on ameliorate the lipidic and glycemic metabolism, thereby improving the function of β‐cells …”

Section: Synthetic Ffar1 Agonists Based On Different Strategiesmentioning

confidence: 99%

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Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Xue

Huang

et al. 2017

Medicinal Research Reviews

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The free fatty acid receptor 1 (FFAR1/GPR40) amplifies glucose-dependent insulin secretion; therefore, it has attracted widespread attention as a promising antidiabetic target. Current clinical proof of concept also indicates that FFAR1 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus (T2DM) without the hypoglycemic risk. Thus, many pharmaceutical companies and academic institutes are competing to develop FFAR1 agonists. However, several candidates have been discontinued in clinical trials, often without reporting the underlying reasons. Herein, we review the challenges and corresponding strategies chosen by different medicinal chemistry teams to improve the physicochemical properties, potency, pharmacokinetics, and safety profiles of FFAR1 agonists, with a brief introduction to the biology and pharmacology of related targets.

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“…The key receptors involve in this beneficial effects are the G protein-coupled receptor (GRP), specifically the selective GRP40 and GRP120, which has been proposed has possible therapeutic targets for insulin resistance and metabolic inflammation [ 97 , 98 ]. In fact, administration of a GRP40 agonist (Yhhu4488) promotes high expression of glucagon-like peptide-1 (GLP-1), decreased fasting blood glucose level, improved β -cell function and lipid homeostasis in type 2 diabetic ob/ob mice [ 99 ]. Also, GRP120 stimulation by a selective agonist improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis in a DIO mice model [ 100 ].…”

Section: Potential Treatments For Inflammation In Metabolic Relatementioning

confidence: 99%

Central Modulation of Neuroinflammation by Neuropeptides and Energy-Sensing Hormones during Obesity

Maldonado-Ruiz

Fuentes-Mera

Camacho

2017

BioMed Research International

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Central nervous system (CNS) senses energy homeostasis by integrating both peripheral and autonomic signals and responding to them by neurotransmitters and neuropeptides release. Although it is previously considered an immunologically privileged organ, we now know that this is not so. Cells belonging to the immune system, such as B and T lymphocytes, can be recruited into the CNS to face damage or infection, in addition to possessing resident immunological cells, called microglia. In this way, positive energy balance during obesity promotes an inflammatory state in the CNS. Saturated fatty acids from the diet have been pointed out as powerful candidates to trigger immune response in peripheral system and in the CNS. However, how central immunity communicates to peripheral immune response remains to be clarified. Recently there has been a great interest in the neuropeptides, POMC derived peptides, ghrelin, and leptin, due to their capacity to suppress or induce inflammatory responses in the brain, respectively. These may be potential candidates to treat different pathologies associated with autoimmunity and inflammation. In this review, we will discuss the role of lipotoxicity associated with positive energy balance during obesity in proinflammatory response in microglia, B and T lymphocytes, and its modulation by neuropeptides.

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Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models

Cited by 14 publications

References 23 publications

Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Central Modulation of Neuroinflammation by Neuropeptides and Energy-Sensing Hormones during Obesity

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