Knocking out DMH neuropeptide Y in mice improved multiple factors like food intake and triggered brown fat adipogenesis.

A team at the Johns Hopkins University School of Medicine has found that knocking out NPY expression in the dorsomedial nucleus of the hypothalamus (DMH) led to experimental rats eating less, using more energy, and accumulating less fat. In these knockout animals brown fat also replaced white fat in certain body areas.

The research is published in Cell Metabolism in a paper titled “Knockout of NPY Expression in the Dorsomedial Hypothalamus Promotes Development of Brown Adipocytes and Prevents Diet-Induced Obesity.”

NPY in the arcuate nucleus (ARC) region of the hypothalamus has previously been shown to be involved in energy regulation, report Sheng Bi, M.D., associate professor of psychiatry and behavioral sciences at Johns Hopkins, and colleagues. Meanwhile, observations that DMH lesions result in hypophagia and decreased body weight indicate that this region of the hypothalamus also plays a role in maintaining energy homeostasis.

Although NPY is expressed by neurons within the DMH, its function in this region of the brain remains unclear. NPY in the ARC is under the control of leptin, but NPY in the DMH is leptin-independent, suggesting that different neuronal mechanism are involved.

Previous work by Dr. Bi’s team has shown that viral vector-induced overexpression of NPY in the DMH of lean rats leads to increased food intake and body weight and exacerbated diet-induced obesity. The researchers now report on studies in which they used an AAV-mediated RNAi to specifically knock down NPY expression in the DMH of rats.

Their results showed that compared with control animals, DMH NPY knockout rats maintained on a diet of regular chow demonstrated a small but significant decrease in body weight gain over the initial few weeks after vector administration. The relative reduction in weight gain was significantly greater, however, when both groups of animals were fed a high fat diet. Whereas control rats fed high fat gained 35% more weight compared with control rats fed regular chow, NPY knockout rats fed a high fat diet gained far less weight than their chow-fed counterparts.

Moreover, NPY knockouts demonstrated significantly reduced hyperphagia when given a high fat diet. When knockout and control rats were given high fat food, both groups initially increased their daily intake dramatically. However, while control rats on high fat remained hyperphagic, NPY knockout rats fed the same high fat diet normalized their energy intake within four weeks.

Interestingly, knocking out NPY in the DMH also appeared to impact glucose homeostasis and enhanced insulin sensitivity. While oral glucose administration resulted in similar patterns of glucose clearance in both the control and NPY knockout rats fed regular chow, “we found that DMH NPY knockout enhanced insulin sensitivity, improved glucose tolerance, and prevented diet-induced hyperglycemia and hyperinsulinemia,” the authors write.

One of the major findings was that knocking out DMP NPY appeared to trigger the formation of brown fat. The researchers found that subcutaneous inguinal fat mass was significantly decreased in NPY knockout rats fed regular chow but it also appeared significantly darker than in control rats.

Further evaluation of fat tissue markers suggested that in fact DMH NPY knockout contributed both to reducing high fat diet-induced white fat adipogenesis while triggering brown adipogenesis in inguinal tissue, perhaps by stimulating brown fat stem cells in white fat tissue. “If we could get the human body to turn ‘bad fat’ into ‘good fat’ that burns calories instead of storing them, we could add a serious new tool to tackle the obesity epidemic in the U.S.,” Dr. Bi points out.

On top of this, NPY knockout rats demonstrated increased activity, particularly during periods of darkness. Calorimetry tests confirmed that these animals were expending significantly more energy both during dark and light phases.

“These results indicate that orexigenic NPY in the DMH normally serves as a key factor in maintaining energy homeostasis and also point to the DMH as a potential target site for therapies aimed at combating obesity and/or diabetes,” the authors conclude.

They further note that although the link between NPY downregulation and glucose homeostasis may have been direct, it could also have been a consequence of the brown adipocyte formation in inguinal fat, the activation of interscapular brown adipose tissue, and the resulting increase in thermogenesis. “The mechanisms through which DMH NPY acts to affect insulin action and regulate glucose levels merit further investigation,” the team suggests.

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