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

Santos, Giovanna Leite ; Dias Costa, Ericka Francislaine ; Dalla Costa, Ana Paula ; Zanesco, Ariane Maria ; Simoes, Marcela Reymond ; Rogério, Fábio ; Demolin, Daniele Masselli Rodrigues ; Navarro, Claudia Daniele Carvalho ; Velloso, Lício Augusto and Francisco, Annelise LU orcid , et al. (2024) In Hormone and Metabolic Research
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... (More)

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 Il1β, 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.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
brown adipose tissue, glucose homeostasis, high fat diet, hypothalamic inflammation, NADPH, nicotinamide nucleotide transhydrogenase
in
Hormone and Metabolic Research
publisher
Georg Thieme Verlag
external identifiers
  • scopus:85209379009
  • pmid:39481390
ISSN
0018-5043
DOI
10.1055/a-2420-6549
language
English
LU publication?
yes
id
54336d29-4d9d-40cd-8840-bd8eb234eacb
date added to LUP
2025-02-17 14:34:57
date last changed
2025-07-08 02:17:07
@article{54336d29-4d9d-40cd-8840-bd8eb234eacb,
  abstract     = {{<p>The mitochondrial protein NAD(P) <sup>+</sup> 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<sup>+</sup> / <sup>+</sup> mice presented a greater mass and a higher whole-tissue ex-vivo oxygen consumption rate. Also, HFD increased the expression of the inflammatory markers Il1β, Tlr4 and Iba1 in the hypothalamus of Nnt<sup>–/–</sup> 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.</p>}},
  author       = {{Santos, Giovanna Leite and Dias Costa, Ericka Francislaine and Dalla Costa, Ana Paula and Zanesco, Ariane Maria and Simoes, Marcela Reymond and Rogério, Fábio and Demolin, Daniele Masselli Rodrigues and Navarro, Claudia Daniele Carvalho and Velloso, Lício Augusto and Francisco, Annelise and Castilho, Roger Frigério}},
  issn         = {{0018-5043}},
  keywords     = {{brown adipose tissue; glucose homeostasis; high fat diet; hypothalamic inflammation; NADPH; nicotinamide nucleotide transhydrogenase}},
  language     = {{eng}},
  publisher    = {{Georg Thieme Verlag}},
  series       = {{Hormone and Metabolic Research}},
  title        = {{Influence of Mitochondrial NAD(P)<sup>+</sup> Transhydrogenase (NNT) on Hypothalamic Inflammation and Metabolic Dysfunction Induced by a High-Fat Diet in Mice}},
  url          = {{http://dx.doi.org/10.1055/a-2420-6549}},
  doi          = {{10.1055/a-2420-6549}},
  year         = {{2024}},
}