Neuropeptide Y (NPY) in the dorsomedial hypothalamus (
DMH) plays an important role in the regulation of energy balance. While
DMH NPY overexpression causes
hyperphagia and
obesity in rats, knockdown of NPY in the
DMH via adeno-associated virus (AAV)-mediated RNAi (AAVshNPY) ameliorates these alterations. Whether this knockdown has a
therapeutic effect on
obesity and glycemic disorder has yet to be determined. The present study sought to test this potential using a rat model of high-fat diet (HFD)-induced
obesity and
insulin resistance, mimicking human
obesity with impaired
glucose homeostasis. Rats had ad libitum access to rodent regular chow (RC) or HFD. Six weeks later, an oral
glucose tolerance test (OGTT) was performed for verifying HFD-induced
glucose intolerance. After verification, obese rats received bilateral
DMH injections of AAVshNPY or the control vector AAVshCTL, and OGTT and
insulin tolerance test (ITT) were performed at 16 and 18 wk after viral injection (23 and 25 wk on HFD), respectively. Rats were killed at 26 wk on HFD. We found that AAVshCTL rats on HFD remained hyperphagic, obese,
glucose intolerant, and
insulin resistant relative to lean control RC-fed rats receiving
DMH injection of AAVshCTL, whereas these alterations were reversed in NPY knockdown rats fed a HFD. NPY knockdown rats exhibited normal food intake,
body weight,
glucose tolerance, and
insulin sensitivity, as seen in lean control rats. Together, these results demonstrate a therapeutic action of
DMH NPY knockdown against
obesity and impaired
glucose homeostasis in rats, providing a potential target for the treatment of
obesity and diabetes.