TGF-beta 1 down-regulation in the mediobasal hypothalamus attenuates hypothalamic inflammation and protects against diet-induced obesity

Author(s)

Mendes, Natalia F. ^{[1, 2]} ; Gaspar, Joana M. ^{[3, 2, 4]} ; Lima-Junior, Jose C. ^{[3, 2]} ; Donato, Jr., Jose ^[5] ; Velloso, Licio A. ^{[3, 2]} ; Araujo, Eliana P. ^{[1, 2]}

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Sch Nursing, Rua Tessalia Vieira Camargo 126, BR-13083887 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, UNICAMP, Obes & Comorbid Res Ctr, Lab Cell Signaling, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, UNICAMP, Fac Med Sci, Campinas, SP - Brazil

^[4] Fed Univ Santa Catarina UFSC, Dept Biochem, Postgrad Program Biochem, Florianopolis, SC - Brazil

^[5] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508000 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: METABOLISM-CLINICAL AND EXPERIMENTAL; v. 85, p. 171-182, AUG 2018.
• Web of Science Citations: 7

Abstract

Background: The consumption of large amounts of dietary fats induces hypothalamic inflammation and impairs the function of the melanocortin system, leading to a defective regulation of caloric intake and whole-body energy expenditure. In mice fed a high-fat diet (HFD), TCF-beta 1 expression was increased and NF-kappa B signaling was activated in proopiomelanocortin neurons, which plays an important role in the obesity-associated hypothalamic inflammation scenario. However, whether excessive hypothalamic TGF-beta 1 impairs energy homeostasis remains unclear. Objectives: We aimed to investigate the role of diet-induced hypothalamic TGF-beta 1 on inflammation and whole-body energy homeostasis. Methods: A TGF-beta 1 inhibitory lentiviral shRNA particle was stereotaxically injected bilaterally in the arcuate nucleus (ARC) of C57BL/6 mice fed a HFD. We assessed changes in body mass and adiposity, food intake, inflammatory markers, and the function of energy and glucose metabolism. Results: TGF-beta 1 down-regulation in the ARC-attenuated body-mass gain, reduced fat-mass accumulation, decreased hypothalamic inflammatory markers, and protected against HFD-induced lipohypertrophy of brown adipose tissue. In addition, the inhibition of hypothalamic TGF-beta 1 increased the locomotor activity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum triglyceride levels. No changes were observed in food intake and glucose homeostasis. Conclusion: Hypothalamic TGF-beta 1 down-regulation attenuates hypothalamic inflammation and improves energy metabolism, resulting in lower body-mass gain and lower fat-mass accumulation, which protects mice from the development of obesity. Our data suggest that modulation of hypothalamic TGF-beta 1 expression might be an effective strategy to treat obesity. (C) 2018 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 17/02983-2 - The role of growth hormone in the brain: relevance for neural functions and in disease
• Grantee: Jose Donato Junior
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/10078-2 - Effect of a high caloric diet in the expression of Hypoxia- inducible factor-1 (HIF1): Role in obesity through deregulation of pomc gene
• Grantee: Joana Margarida Navalho Gaspar
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/17810-3 - Evaluation of TGF-b1 function in the hypothalamus of animals with obesity and diabetes induced by high-fat diet
• Grantee: Natália Ferreira Mendes
• Support Opportunities: Scholarships in Brazil - Doctorate