Obesity is a large and growing global health problem with few effective therapies. The present study investigated metabolic and physiological benefits of nicotinamide N-methyltransferase inhibitor (NNMTi) treatment combined with a lean diet substitution in diet-induced obese mice. NNMTi treatment combined with lean diet substitution accelerated and improved body weight and fat loss, increased whole-body lean mass to body weight ratio, reduced liver and epididymal white adipose tissue weights, decreased liver adiposity, and improved hepatic steatosis, relative to a lean diet substitution alone. Importantly, combined lean diet and NNMTi treatment normalized body composition and liver adiposity parameters to levels observed in age-matched lean diet control mice. NNMTi treatment produced a unique metabolomic signature in adipose tissue, with predominant increases in ketogenic amino acid abundance and alterations to metabolites linked to energy metabolic pathways. Taken together, NNMTi treatment’s modulation of body weight, adiposity, liver physiology, and the adipose tissue metabolome strongly support it as a promising therapeutic for obesity and obesity-driven comorbidities.

Food intake is a complex behavior regulated by discrete brain nuclei that integrate homeostatic nutritional requirements with the hedonic properties of food. Homeostatic feeding (i.e. titration of caloric intake), is typically associated with hypothalamic brain nuclei, including the paraventricular nucleus of the hypothalamus (PVN). Hedonic feeding is driven, in part, by the reinforcing properties of highly palatable food (HPF), which is mediated by the nucleus accumbens (NAc). Dysregulation of homeostatic and hedonic brain nuclei can lead to pathological feeding behaviors, namely overconsumption of highly palatable food (HPF), that may drive obesity. Both homeostatic and hedonic mechanisms of food intake have been attributed to several brain regions, but the integration of homeostatic and hedonic signaling to drive food intake is less clear, therefore we aimed to identify the neuroanatomical, functional, and behavioral features of a novel PVN → NAc circuit. Using viral tracing techniques, we determined that PVN → NAc has origins in the parvocellular PVN, and that PVN → NAc neurons express VGLUT1, a marker of glutamatergic signaling. Next, we pharmacogenetically stimulated PVN → NAc neurons and quantified both gamma-aminobutyric acid (GABA) and glutamate release and phospho-cFos expression in the NAc and observed a robust and significant increase in extracellular glutamate and phospho-cFos expression. Finally, we pharmacogenetically stimulated PVN → NAc which decreased intake of highly palatable food, demonstrating that this glutamatergic circuitry regulates aspects of feeding.