Neuropeptide Y in the noradrenergic neurons induces the development of cardiometabolic diseases in a transgenic mouse model

Abstract

Neuropeptide Y (NPY) is a neuropeptide widely expressed in the brain and a peptide transmitter of sympathetic nervous system (SNS) co-released with noradrenaline (NA) in prolonged stress. Association of a gain-of-function polymorphism in the human NPY gene with dyslipideamia, diabetes and vascular diseases suggests that increased NPY plays a role in the pathogenesis of the metabolic syndrome in humans. In the hypothalamus, NPY plays an established role in the regulation of body energy homeostasis. However, the effects of NPY elsewhere in the brain and in the SNS are less explored. In order to understand the role of NPY co-expressed with NA in the sympathetic nerves and brain noradrenergic neurons, a novel mouse model overexpressing NPY in noradrenergic neurons was generated. The mouse displays metabolic defects such as increased adiposity, hepatosteatosis, and impaired glucose tolerance as well as stress-related hypertension and increased susceptibility to vascular wall hypertrophy. The mouse phenotype closely reflects the findings of the several association studies with human NPY gene polymorphisms, and fits with the previous work on the effects of stress-induced NPY release on metabolism and vasculature. Thus, in addition of promoting feeding and obesity in the hypothalamus, NPY expressed in the noradrenergic neurons in the brain and in the SNS induces the development of cardiometabolic diseases.

Vglut2-based glutamatergic signaling in central noradrenergic neurons is dispensable for normal breathing and chemosensory reflexes

“…Neuropeptide Y (NPY) and galanin have been shown to co-exist in LC NA neurons and are involved in regulating energy metabolism, stress, or anxiety (Ruohonen et al, 2012;Tasan et al, 2010;Weinshenker and Holmes, 2016). In our studies, we account for potential metabolic changes that may underlie or be coordinate with changes in breathing.…”

“…Fourth, it is possible that another neurotransmitter/neuropeptide within NA neurons might be released in higher amounts in Dbh-Cre; Vglut2 cKO mice to compensate for the deficiency of glutamate in breathing. Neuropeptide Y (NPY) and galanin have been shown to co-exist in LC NA neurons and are involved in regulating energy metabolism, stress, or anxiety (Ruohonen et al, 2012; Tasan et al, 2010; Weinshenker and Holmes, 2016). In our studies, we account for potential metabolic changes that may underlie or be coordinate with changes in breathing.…”