Biased signaling via NtsR1 restrains food intake and weight gain in obese mice
Ramirez-Virella, J.; Black, K.; Dennis, N. F.; Bugescu, R.; Thompson, K.; Olsen, S. H.; Slosky, L. M.; McElligott, Z. A.; Leinninger, G. M.
Show abstract
Neurotensin receptor 1 (NTSR1) activation suppresses feeding and promotes weight loss but is limited by adverse effects associated with Gq signaling. SBI-553 is a {beta}-arrestin-biased allosteric modulator of NTSR1 that avoids these effects. We evaluated the effects of SBI-553 (5 or 12 mg/kg, i.p.) on food intake and body weight in lean and diet-induced obese mice. Neither dose altered metabolic parameters, locomotor activity, or wheel running. SBI-553 did not affect ad libitum feeding in lean mice; however, both doses acutely reduced high-fat diet intake in obese mice. While 5 mg/kg had no effect on hunger-induced feeding, 12 mg/kg suppressed refeeding in both chow- and high-fat-fed mice of both sexes and reduced weight regain in obese mice. These findings identify SBI-553 as a potential strategy for reducing food intake and supporting weight loss.
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