Alteration of the leptin network in late morbid obesity induced in mice bybrain infection with canine distemper virus

Viruses can induce progressive neurologic disorders associated with diverse pathological manifestations, and therefore, viral infection of the brain c an impair differentiated neural functions, depending on the initial viral t ropism. We have previously reported that canine distemper virus (CDV) targe ts certain mouse brain structures, including the hypothalamus, early and se lectively. Infected mice exhibit acute encephalitis, with late disease, cha racterized by motor impairment or obesity syndrome, appearing in some of th e surviving mice several months after the initial viral replication. In the present study, we show viral persistence in the hypothalami of obese mice, as demonstrated by low, but still significant, levels of CDV nucleoprotein transcripts, associated with a dramatic decrease in F gene mRNAs. Given th e pivotal role of the hypothalamus in obesity (eating behavior, energy cons umption, and neuroendocrine function) and that of leptin, the adipose tissu e-derived satiety factor acting through hypothalamic receptors, we analyzed the leptin networks in both obese and nonobese mice. The discrepancy found between the chronic and dramatic increase in blood leptin levels and the o ccurrence of obesity may be due to leptin resistance in the brain. In fact, expression of the long leptin receptor isoform, representing the functiona l leptin receptor, was specifically downregulated in the hypothalami of obe se mice, explaining their inability to generate an adequate response to lep tin in the brain. Intriguingly, during the acute phase of infection, its ex pression was increased in CDV-targeted structures in all infected mice and remained high in obese mice in all CDV-targeted structures, except for the hypothalamus. The biphasic change in hypothalamic leptin receptor expressio n seen during the progression of CDV-induced obesity provides a new paradig m for understanding mechanisms of neuroendocrinological, virus-induced abno rmalities.