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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Diabetes: Molecular Mechanisms
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1511813
This article is part of the Research Topic Advances in β-cell Development & Regeneration View all articles

Hepatocyte Nuclear Factor 4-α (HNF4α) is necessary for High Fat Diet (HFD)-induced pancreatic β-cell mass expansion and metabolic compensations

Provisionally accepted
Francieli Caroline De Ramos Francieli Caroline De Ramos 1Robson Barth Robson Barth 1Marcos Rizzon Santos Marcos Rizzon Santos 1Milena dos Santos Almeida Milena dos Santos Almeida 1Sandra Ferreira Sandra Ferreira 2Alex Rafacho Alex Rafacho 1Antonio Boschiero Antonio Boschiero 2Gustavo J Santos Gustavo J Santos 1*
  • 1 Federal University of Santa Catarina, Florianopolis, Brazil
  • 2 State University of Campinas, Campinas, São Paulo, Brazil

The final, formatted version of the article will be published soon.

    Aims: This study investigates the role of Hepatocyte Nuclear Factor 4α (HNF4α) in the adaptation of pancreatic β-cells to an HFD-induced obesogenic environment, focusing on β cell mass expansion and metabolic adaptations. Main methods: We utilized an HNF4α knockout (KO) mouse model, with CRErecombinase enzyme activation confirmed through tamoxifen administration. KO and Control (CTL) mice were fed an HFD for 20 weeks. We monitored body weight, food intake, glucose tolerance, insulin sensitivity, and insulinemia. Also, to assess structural and metabolic changes, histological analyses of pancreatic islets and liver tissue were conducted. Key findings: KO mice displayed lower fasting blood glucose levels compared to CTL mice after tamoxifen administration, indicating impaired glucoseregulated insulin secretion. HFD-fed KO mice consumed less food but exhibited greater weight gain and perigonadal fat accumulation, reflecting higher energy efficiency. Histological analysis revealed more pronounced liver steatosis and fibrosis in KO mice on HFD. Glucose intolerance and insulin resistance were exacerbated in KO mice, highlighting their inability to adapt to increased metabolic demand. Structural analysis showed that KO mice failed to exhibit HFD-induced β cell mass expansion, resulting in reduced islet diameter and number, confirming the critical role of HNF4α in β cell adaptation. Significance: This study demonstrates that HNF4α is essential for the proper metabolic and structural adaptation of pancreatic β-cells in response to an obesogenic environment. The lack of HNF4α impairs β cell functionality, leading to increased susceptibility to glucose intolerance and insulin resistance. These findings underscore the importance of HNF4α in maintaining glucose homeostasis and highlight its potential as a therapeutic target for diabetes management in obesity.

    Keywords: β-cell replacement, HNF4α, β-Cell mass expansion, Obesity, β-Cell regeneration

    Received: 15 Oct 2024; Accepted: 04 Dec 2024.

    Copyright: © 2024 De Ramos, Barth, Santos, Almeida, Ferreira, Rafacho, Boschiero and Santos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Gustavo J Santos, Federal University of Santa Catarina, Florianopolis, Brazil

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