ObjectiveType 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight.MethodsWe investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice.ResultsTAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls.ConclusionsWe have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity.

Background and Purpose Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L‐cells located predominantly in distal regions of the gut secrete glucagon‐like peptide 1 (GLP‐1) and peptide tyrosine‐tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L‐cells stimulated by the BA receptor G protein‐coupled bile acid receptor 1 (GPBAR1). Experimental Approach A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L‐cell secretion in vitro and in vivo in mice and monkey. In analogy to BA, RO5527239 was conjugated with taurine to reduce p.o. bioavailability yet retaining its potency. Using RO5527239 and tauro‐RO5527239, the acute secretion effects on L‐cells were addressed via different routes of administration. Key Results GPBAR1 signalling triggers the co‐secretion of PYY and GLP‐1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro‐RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys. Conclusion and Implications Selective GPBAR1 activation elicits a strong secretagogue effect on L‐cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal‐distal loop that mediates the early phase of nutrient‐evoked L‐cell secretion effects.

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Background The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance (IR). However, the concept remains controversial; it has been debated whether MetS represents nothing more than simultaneous co-occurrence of individual risk factors, or whether there are common, shared pathophysiologic mechanisms that link the individual components. Methods and Results To investigate the emergence of metabolic and cardiovascular components during the development of MetS, we identified MetS-predisposed animals (n=35) in a large population of rhesus macaques (Macaca mulatta, 12.7 ± 2.9 years old, n=408), acclimated them to standardized conditions, and monitored the progression of individual component features over 18 months. In total 18 MetS animals with recently developed fasting hyperinsulinemia, central obesity, hypertension, and atherogenic dyslipidemia, we found that individual metabolic and cardiovascular components track together during the transition from pre-MetS to onset of MetS; MetS was associated with a 60% impairment of flow mediated dilation (FMD), establishing the mechanistic link with vascular dysfunction. Pioglitazone treatment (3 mg/kg body weight/day for 6 weeks), a PPARγ agonist, reversibly improved atherogenic dyslipidemia and IR, and fully restored FMD with persistent benefits. Conclusions Co-emergence of metabolic and cardiovascular components during MetS progression and complete normalization of vascular dysfunction with PPARγ agonists suggest shared underlying mechanisms rather than separate processes, arguing for the benefit of early intervention of MetS components. Predictive NHP models of MetS should be highly valuable in mechanistic and translational studies on the pathogenesis of MetS in relation to cardiovascular disease and diabetes.

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