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

Giovanna Leite Santos; Ericka Francislaine Dias Costa; Ana Paula Dalla Costa; Ariane Maria Zanesco; Marcela Reymond Simoes; Fábio Rogério; Daniele Masselli Rodrigues Demolin; Claudia Daniele Carvalho Navarro; Lício Augusto Velloso; Annelise Francisco; Roger Frigério Castilho

doi:10.1055/a-2420-6549

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2025; 57(03): 199-207
DOI: 10.1055/a-2420-6549

Original Article: Endocrine Care

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

Giovanna Leite Santos

¹Department of Pathology, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Ericka Francislaine Dias Costa

¹Department of Pathology, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Ana Paula Dalla Costa

¹Department of Pathology, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Ariane Maria Zanesco

²Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Marcela Reymond Simoes

²Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Fábio Rogério

¹Department of Pathology, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Daniele Masselli Rodrigues Demolin

³Multidisciplinary Center for Biological Investigation on Laboratory Animals Science, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Claudia Daniele Carvalho Navarro

¹Department of Pathology, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Lício Augusto Velloso

²Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Annelise Francisco

⁴Department of Experimental Medical Science, Lunds Universitet, Lund, Sweden (Ringgold ID: RIN5193)

¹Department of Pathology, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

,

Roger Frigério Castilho

¹Department of Pathology, State University of Campinas (UNICAMP), Campinas, Brazil (Ringgold ID: RIN28132)

› Author Affiliations

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 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.

Keywords

brown adipose tissue - glucose homeostasis - high fat diet - hypothalamic inflammation - NADPH - nicotinamide nucleotide transhydrogenase

Full Text

References

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Supplementary Material

Supplementary Material

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

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