Influence of Mitochondrial NAD(P) ⁺ Transhydrogenase (NNT) on Hypothalamic Inflammation and Metabolic Dysfunction Induced by a High-Fat Diet in Mice

Author(s):Show less -

Santos, Giovanna Leite ; Costa, Ericka Francislaine Dias ; Dalla Costa, Ana Paula ; Zanesco, Ariane Maria ; Simoes, Marcela Reymond ; Rogerio, Fabio ; Demolin, Daniele Masselli Rodrigues ; Navarro, Claudia Daniele Carvalho ; Velloso, Licio Augusto ; Francisco, Annelise ; Castilho, Roger Frigerio

• Document type: Journal article
• Source: Hormone and Metabolic Research; v. N/A, p. 9-pg., 2024-10-31.

Abstract

The mitochondrial protein NAD(P)(+) transhydrogenase (NNT) has been implicated in the metabolic derangements observed in obesity. Mice with the C57BL/6J genetic background bear a spontaneous mutation in the Nnt gene and are known to exhibit increased susceptibility to diet-induced metabolic disorders. Most of the studies on NNT in the context of diet-induced obesity have compared C57BL/6J mice with other mouse strains, where differences in genetic background can serve as confounding factors. Moreover, these studies have predominantly employed a high-fat diet (HFD) consisting of approximately 60% of calories from fat, which may not accurately mimic real-world fat-rich diets. In this study, we sought to examine the role of NNT in diet-induced hypothalamic inflammation and metabolic syndrome by using a congenic mice model lacking NNT, along with a HFD providing approximately 45% of calories from fat. Our findings indicate that mice lacking NNT were more protected from HFD-induced weight gain but presented a worse performance on glucose tolerance test, albeit not in insulin tolerance test. Interestingly, the brown adipose tissue of HFD-fed Nnt (+/+) mice presented a greater mass and a higher whole-tissue ex-vivo oxygen consumption rate. Also, HFD increased the expression of the inflammatory markers Il1 beta, Tlr4 and Iba1 in the hypothalamus of Nnt (-/-) mice. In conclusion, our study highlights the importance of NNT in the context of diet-induced obesity and metabolic syndrome, indicating its contribution to mitigate hypothalamic inflammation and suggesting its role in the brown adipose tissue increased mass. (AU)

• FAPESP's process: 23/00229-0 - Pathophysiological roles of mitochondrial NAD(P)+ transhydrogenase
• Grantee: Roger Frigério Castilho
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 23/06469-2 - Role of NAD(P)+ transhydrogenase (NNT) in hypothalamic inflammation and brown adipose tissue biogenesis in mice
• Grantee: Ericka Francislaine Dias Costa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants