Lack of NPY in neurotensin neurons leads to a lean phenotype.

Neuropeptide Y (NPY) producing neurons in the arcuate nucleus (Arc) of the hypothalamus are essential to the regulation of food intake and energy homeostasis. Whilst they have classically been thought to co-express agouti-related peptide (AgRP), it is now clear that there is a sub-population of NPY neurons in the Arc that do not. Here, we show that a subset of AgRP-negative, NPY-positive neurons in the Arc also express neurotensin (NTS) and we use an NTS-Cre line to investigate the function of this sub-population of NPY neurons. The lack of NPY in NTS-positive neurons led to a marked reduction in fat mass and bodyweight as well as a significant reduction in food intake in male NPYlox/lox; NTScre/+ mice compared to controls. Despite the reduction in food intake, overall energy expenditure was similar between genotypes due to concomitant reduction in activity in NPYlox/lox; NTScre/+ mice. Furthermore, cortical bone mass was significantly reduced in NPYlox/lox;NTScre/+ mice with no evident alterations in the cancellous bone compartment, likely due to reduced leptin levels as a result of their reduced adiposity. Taken together, these data suggest that the sub-population of Arc NPY neurons expressing NTS are critical for regulating food intake, activity and fat mass but are not directly involved in the control of bone mass.