ECE2024 Oral Communications Oral Communications 12: Diabetes, Obesity, Metabolism and Nutrition | Part II (6 abstracts)
Loss of murine Gpr45 leads to significant obesity due to hyperphagia and hypoactivity
Iqra Mumal 1 , Soo Min 1 , Diana Lee 1 , Jacob Trenish 1 , Dwaine Pryce 1 , Daniel Gomez 1 , Erqian Na 1,Parnian Bigdelou , Judith Altarejos 1 , Mark Sleeman 1 & Jason Mastaitis 1
1Regeneron Pharmaceuticals, Inc., Tarrytown, United States
Monogenic obesity in humans is caused by loss-of-function mutations in several genes, all of which reside in the CNS, and many of which are involved in either leptin signaling or the downstream melanocortin pathway. Ablation of the CNS-specific orphan GPCR Gpr45 in mice is associated with significant monogenic obesity. However, to date, there are no associations between the loss of GPR45 and obesity in human genetics. To that end, we made our own line of Gpr45-/- mice and found, similar to published findings, that Gpr45-/- mice are obese, with significantly increased adiposity. In addition, these mice are hypoactive and have reduced energy expenditure compared to their wildtype counterparts. Interestingly, we also found there were phenotypic differences between the male and female knockout mice, which has not been previously shown. Specifically, we found male Gpr45-/- mice preferentially store fat in their livers, while the female knockouts have large subcutaneous and visceral adipose depots. Accordingly, the male knockouts have significantly increased serum levels of enzymes indicative of liver damage and are significantly more hyperglycemic and insulin-resistant compared to the females. Contrary to prior findings, we discovered that all Gpr45-/- mice exhibit hyperphagia, suggesting both a food intake and metabolic role in their obesity phenotype. Gpr45-/- mice have levels of leptin consistent with their adiposity, suggesting it is not leptin deficiency driving the obesity. Accordingly, administration of setmelanotide, which acts as a melanocortin 4 receptor agonist was effective at reducing food intake in Gpr45-/- mice indicating intact melanocortin signaling downstream of leptin. These results reveal that in mice, Gpr45 is a critical regulator of appetite and metabolism as well as a modulator of lipid storage in peripheral tissues.
Volume 99
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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