Hypothalamic NPY-Y1R Interacts with Gonadal Hormones in Protecting Female Mice against Obesity and Neuroinflammation

We previously demonstrated that Npy1rrfb mice, which carry the conditional inactivation
of the Npy1r gene in forebrain principal neurons, display a sexually dimorphic phenotype, with
male mice showing metabolic, hormonal and behavioral effects and females being only marginally
affected. Moreover, exposure of Npy1rrfb male mice to a high-fat diet (HFD) increased body weight
growth, adipose tissue, blood glucose levels and caloric intake compared to Npy1r2lox male controls.
We used conditional knockout Npy1rrfb and Npy1r2lox control mice to examine whether forebrain
disruption of the Npy1r gene affects susceptibility to obesity and associated disorders of cycling and
ovariectomized (ovx) female mice in a standard diet (SD) regimen or exposed to an HFD for 3 months.
The conditional deletion of the Npy1r gene increased body weight and subcutaneous white adipose
tissue weight in both SD- and HFD-fed ovx females but not in cycling females. Moreover, compared
with ovx control females on the same diet regimen, Npy1rrfb females displayed increased microglia
number and activation, increased expression of Neuropeptide Y (NPY)-immunoreactivity (IR) and
decreased expression of proopiomelanocortin-IR in the hypothalamic arcuate nucleus (ARC). These
results suggest that in the ARC NPY-Y1R reduces the susceptibility to obesity of female mice with
low levels of gonadal hormones and that this effect may be mediated via NPY-Y1R ability to protect
the brain against neuroinflammation.