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Introduction Alströmsyndrome (AS) is an autosomal recessive ciliopathy caused by mutations inALMS1, which encodes a protein that localizes to centrosomes and basal bodies of primary cilia. Early emergence of obesity inpatients withAS suggests a key role for ALMS1 in body weight regulation. Mice with non-functional Alms1 develop normal hypothalamic cilia, but these are not maintained postnatally. This suggests involvement of the central pathways regulating energy balance in the development of obesity in AS. Since leptin signaling has been shown to be impaired in the related ciliopathy Bardet-Biedl syndrome, we hypothesized that targeting central pathways downstream of leptin signaling would reduce food intake and body weight inAlms1-/-mice. Methods Dose-response for the selective melanocortin 1/4 receptor agonist RM-493 (Setmelanotide) in suppressing food intake was determined in 19-wk-old femaleAlms1-/-mice(n=3) and wild-type (WT) littermates (n=3), individually housed and receiving daily intraperitoneal injections of vehicle (3 d) followed by RM-493 (3 d). A separate cohort of 17-wk-old male (n=4) and female (n=4)Alms1-/-mice had food intake measured continuously in metabolic cages(CLAMS, Columbus Instruments). After determining baseline food intake, mice received vehicle (2 d), followed by RM-493 (3 d), then 3d of washout (no treatment). Repeated measures ANOVA was performed. Mean ± SE and nominal p-values are shown. Results In the dose-response study,Alms-/-andWThadfood intake responses that weresimilarfor40(p=0.72),but differentfor100, 250, and 1000 nmol/kg/d (p’s0.84).RM-493(250 nmol/kg/d)reduced food intakein maleAlms1-/- compared to vehicle (-46.4%;p=0.003), causinganonsignificantreduction in body weight(-13.1%;p=0.33),whereasfood intakein femaleAlms1-/-wasreduced by 28.5%,and body weight by 6.5%,althoughneither difference was significant (p’s>0.61).During the washout period, maleAlms1-/-ate 62.8% more food than during the vehicle period(p