Abstract
Transthyretin (TTR) is a blood and cerebrospinal fluid transporter of thyroxine and retinol. Gene expression profiling revealed an elevation of Ttr expression in the dorsomedial hypothalamus (DMH) of rats with exercise-induced anorexia, implying that central TTR may also play a functional role in modulating food intake and energy balance. To test this hypothesis, we have examined the effects of brain TTR on food intake and body weight and have further determined hypothalamic signaling that may underlie its feeding effect in rats. We found that intracerebroventricular (icv) administration of TTR in normal growing rats decreased food intake and body weight. This effect was not due to sickness as icv TTR did not cause a conditioned taste aversion. ICV TTR decreased neuropeptide Y (NPY) levels in the DMH and the paraventricular nucleus (P < 0.05). Chronic icv infusion of TTR in Otsuka Long-Evans Tokushima Fatty rats reversed hyperphagia and obesity and reduced DMH NPY levels. Overall, these results demonstrate a previously unknown anorectic action of central TTR in the control of energy balance, providing a potential novel target for treating obesity and its comorbidities.
Highlights
Obesity has become a public health problem and has been linked to various life-threatening diseases such as cardiovascular disease and type 2 diabetes
To assess whether dorsomedial hypothalamus (DMH) Ttr elevation is a primary cause of exercise or a secondary response to reductions of food intake and body weight, we examined Ttr expression in the DMH of pair-fed (PF) rats
DMH TTR levels did not differ significantly between PF and sedentary rats (SED) rats (Fig. 2e). These results underscore the potential contribution of DMH TTR elevation to exercise-induced reductions in food intake and body weight gain, suggesting that DMH or central TTR may act as an anorectic to affect energy balance
Summary
Obesity has become a public health problem and has been linked to various life-threatening diseases such as cardiovascular disease and type 2 diabetes. Human studies have shown that intense exercise reduces daily energy balance in adolescents with obesity by both increasing energy expenditure and decreasing food consumption[5]. Despite these compelling observations, the neural/molecular mechanisms underlying these effects remain largely unknown. We have demonstrated that exercise reversed the hyperphagia and obesity of OLETF rats[3] Together, these results indicate that exercise limits the orexigenic effects of DMH NPY in OLETF rats, but the molecule(s) mediating these effects remain to be determined[14]. We report that central TTR acts as an anorectic to lower body weight via, at least in port, decreasing hypothalamic NPY signals
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