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LIF and CCBP2 are involved in the regulation of hypothalamic energy homeostasis in mice

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Author(s):
Milena Fioravante
Total Authors: 1
Document type: Doctoral Thesis
Institution: Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Defense date:
Advisor: Lício Augusto Velloso
Abstract

Obesity has reached epidemic proportions and populations in many regions of the world are facing an increase in the prevalence of a number of its comorbidities such as, non-alcoholic fatty liver disease, type 2 diabetes and some types of cancer. Excessive body mass results from the disequilibrium between caloric intake and energy expenditure, which includes, basal metabolism, physical activity and adaptive thermogenesis induced by diet or environmental temperature. Nevertheless, a number of diverse and complex metabolic mechanisms are involved in the control of body mass and many of them are regulated by the central nervous system. Studies have shown that in diet-induced obesity the hypothalamus can be affected by an inflammatory response induced by dietary fats. This inflammation results in defective response to anorexigenic hormones, such as leptin and insulin, and therefore to an abnormal regulation of food intake and energy expenditure. Chemokines are expected to play an important role in the regulation of the inflammatory response in the hypothalamus, which is observed as early as 24 h after the introduction of a high-fat diet. The chemokines are involved in the recruitment of inflammatory cells to the site of inflammation. We believe that the identification and characterization of factors involved in the early steps of hypothalamic inflammation in obesity may contribute for the understanding of the pathophysiological mechanisms leading to obesity. The objective of this study was to evaluate the expression of hypothalamic chemokines during early experimental obesity induced by the consumption of a high-fat diet. In the first part of the study, we used PRC-array to identify LIF and CCBP2 as two chemokines potentially involved in the regulation of the hypothalamic inflammatory response during early exposure to dietary fats. LIF is increased in the hypothalamus of obese resistant (OR) mice. Upon immunoneutralization of hypothalamic LIF, OR mice presented increased body mass and reduction of glucose tolerance, becoming phenotypically similar to obese prone (OP) mice. In addition, in OR mice treated with the anti-LIF antibody in the hypothalamus, there were reduced spontaneous physical activity and increased expression of inflammatory cytokines in the hypothalamus, as early as one day after the introduction of a high-fat diet. Regarding CCBP2, we determined using real-time PCR that the transcript encoding for this chemokine is reduced in the hypothalamus of OP mice. A letivirus vector was constructed to increase the expression of CCBP2 and this was used to treat OP mice via hypothalamic injection. The increased expression of CCBP2 in the hypothalamus of OP mice was accompanied by reduction of diet-induced expression of inflammatory cytokines in the hypothalamus. This was not accompanied by changes in body mass; however, there was an improvement of whole body glucose tolerance as compared with respective controls (AU)

FAPESP's process: 12/20115-4 - THE EXPRESSION OF CHEMOKINES IN DIET-INDUCED INFLAMMATION OF THE HYPOTHALAMUS IN EXPERIMENTAL OBESITY
Grantee:Milena Fioravante de Camargo
Support type: Scholarships in Brazil - Doctorate