Hypothalamic Nlhlh2 protein connects the obese phenotype with behavioral changes

Author(s)

Rodrigo Scarpari Carraro

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2021-04-28

Examining board members

Licio Augusto Velloso; José Donato Júnior; Rodrigo Ferreira de Moura; Patricia Aline Boer; Marciane Milanski Ferreira

• Advisor: Licio Augusto Velloso

Abstract

Nescient helix-loop-helix-2 (Nhlh2) is a transcription factor highly expressed in the hypothalamus where it controls the transcription of prohormone convertase 1/3, therefore impacting on the processing of POMC and thus, on whole body energy homeostasis. Experimental studies have shown that knockout of the Nhlh2 gene results in increased body mass, reduced physical activity and hypogonadism. In humans, at least one polymorphism of NHLH2 gene is associated with obesity; and, in Prader-Willi syndrome, a rare human condition characterized by obesity, hypogonadism and behavioral abnormalities, the expression of NHLH2 is reduced. Despite considerable clinical and experimental evidence suggesting that NHLH2 could be a good target for the treatment of obesity, no previous study has evaluated the impact of a hypothalamic overexpression of Nhlh2 in obesity. Here, we used a lentivirus that induced 40% increase in the hypothalamic expression of Nhlh2 and evaluated metabolic parameters in an experimental model of diet-induced obesity. In mice fed a high-fat diet introduced right after the bilateral arcuate nucleus intracerebroventricular injection of the lentivirus, the hypothalamic overexpression of Nhlh2 prevented the development of obesity by a mechanism dependent predominantly on the reduction of caloric intake. When hypothalamic overexpression of Nhlh2 was induced in previously obese mice, the beneficial impact on obesity-associated phenotype was even greater; thus, there was an 80% attenuation in body mass gain, reduced whole body adiposity, increased brown adipose tissue temperature, reduced hypothalamic inflammation and reduced liver steatosis. In this setting, the beneficial impact of hypothalamic overexpression of Nhlh2 was a result of combined effects on caloric intake, energy expenditure and physical activity. Moreover, the hypothalamic overexpression of Nhlh2 reduced obesity-associated anxiety/depression behavior. Thus, this study provides an experimental proof-of-concept supporting that hypothalamic Nhlh2 is a good target for the treatment of obesity (AU)

• FAPESP's process: 16/00977-2 - Evaluation of expression and distribution of Nhlh2 protein in the hypothalamus of animals subjected to high fat diet
• Grantee: Rodrigo Scarpari Carraro
• Support Opportunities: Scholarships in Brazil - Doctorate