Background and PurposeObesity and associated co‐morbidities, such as type 2 diabetes and non‐alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co‐morbidities.Experimental ApproachThe effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP‐089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weight‐independent effects of KBP‐089 using a weight‐matched group.Key ResultsRats fed a high‐fat diet were treated, s.c., with KBP‐089 0.625, 1.25, 2.5 μg·kg−1or vehicle. KB‐089 induced in a dose‐dependent and sustained weight loss (~17% by 2.5 μg·kg−1). Moreover, KBP‐089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP‐089 improved glucose homeostasis through improved insulin action. To obtain a weight‐matched group, significantly less food was offered (9% less than in the KBP‐089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBP‐089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBP‐089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle.Conclusions and ImplicationsThe novel DACRA, KBP‐089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet‐induced weight loss.