Obesity has become an important health problem and its prevalence is highly increasing. Pharmacotherapy alone or in combination with either lifestyle modification or surgery, is consistent in maintaining a healthy body weight, and preventing progression to obesity-related diseases. However, the anti-obesity drugs are limited by non-specificity and unsustainable weight loss effects. Therefore, further research is needed to develop new preventive and treatment approaches against obesity. Here we targeted the brain lipid metabolism as a promising strategy. In the brain, the hypothalamus harbors specialized functional circuits in the physiological regulation of calories intake and spend. Importantly, some enzymes involved in fatty acid metabolism are highly expressed in the hypothalamus. We took advantage of the C75-CoA, a strong competitive inhibitor of carnitine palmitoyltransferase 1A (CPT1A) that catalyzes the rate-limiting step of fatty-acid oxidation.
Nanomedicine-based approaches hold promise for improved brain distribution of drugs. We developed an ingenious crosslinked polymeric micelle that can stably load the C75-CoA for in vivo application.
Intracerebroventricular administration of the nanomedicine resulted in the reduction of food intake and body weight compared with the free drug. This satiating effect seemed to be regulated by the appetite-related neuropeptides and specific hypothalamic nuclei activation. Altogether, this study might contribute to the development of a new generation of nanomedicine-based approaches targeting brain to prevent obesity.