Defective neurocircuit activity within the hypothalamic arcuate nucleus (ARC) , a crucial brain area for the regulation of metabolism, is implicated in obesity pathogenesis. Perineuronal nets (PNNs) are extracellular matrix structures that regulate neurocircuit activity, and PNN loss can adversely influence the activity of the enmeshed neurons. To determine if defective ARC PNNs might contribute to obesity, we first quantified PNN abundance in obese mice induced by consuming a high-fat high-sucrose diet (HFHS; Bio-Serv #F4997) 12 wk. We found that compared to chow-fed controls, HFHS diet feeding caused an 84.3% decrease (p<0.0001) in the abundance of PNNs enmeshing ARC neurons. This loss was also associated with increases of ARC microgliosis (1.5-fold; p=0.004) and astrogliosis (2.9-fold; p=0.006) , suggesting a link between ARC PNN loss and glial activation. To translate these findings to humans, we analyzed postmortem hypothalamic samples from 9 subjects (Sex, 7M/2F; Age, 22-71y) that had previously undergone quantitative T2 magnetic resonance imaging (MRI) to assess obesity-associated hypothalamic gliosis. Consistent with our findings in mice, ARC PNN content was strongly and inversely correlated with the hypothalamic gliosis score measured by T2-weighted MRI imaging (R2=0.63, p=0.01) . To assess whether this depletion of ARC PNNs might contribute to obesity, we microinjected either the PNN-digesting enzyme, ChABC, or heat-inactivated ChABC control, into the rat ARC at the onset of a 4 wk HFHS dietary intervention. We found that compared to controls, the magnitude of diet-induced hyperphagia (17%; p<0.0001) , weight gain (41%; p<0.0001) , and excess body fat accumulation (28%; p=0.01) increased following PNN digestion, driven largely by increased dark cycle food intake (24%; p=0.006) . These findings collectively identify ARC PNNs as novel participants in the central control of energy homeostasis, and implicate their loss as a potential contributor to obesity pathogenesis.
K.M.Alonge: None. G.J.Morton: Research Support; Novo Nordisk A/S. E.Schur: None. J.Thaler: None. M.W.Schwartz: None. M.D.Dorfman: None. J.M.Scarlett: None. S.J.Melhorn: None. Y.Ye: None. S.J.W.Hu: None. K.L.Francis: None. A.Hendrickson: None. K.Cui: None.