Hepatocyte nuclear factor 4-α is necessary for high fat diet-induced pancreatic β-cell mass expansion and metabolic compensations.

IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Frontiers in Endocrinology Pub Date : 2024-12-17 eCollection Date: 2024-01-01 DOI:10.3389/fendo.2024.1511813
Francieli Caroline de Ramos, Robson Barth, Marcos Rizzon Santos, Milena Dos Santos Almeida, Sandra Mara Ferreira, Alex Rafacho, Antônio Carlos Boschero, Gustavo Jorge Dos Santos
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Abstract

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 CRE-recombinase 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 glucose-regulated 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.

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肝细胞核因子4-α是高脂肪饮食诱导的胰腺β细胞团扩增和代谢代偿所必需的。
目的:本研究探讨肝细胞核因子4α (HNF4α)在胰腺β细胞适应hfd诱导的肥胖环境中的作用,重点关注β细胞的质量扩增和代谢适应。主要方法:采用HNF4α敲除(KO)小鼠模型,通过给药他莫昔芬证实cre -重组酶激活。对照组(CTL)和对照组(KO)小鼠分别饲喂HFD 20周。我们监测了体重、食物摄入、葡萄糖耐量、胰岛素敏感性和胰岛素血症。此外,为了评估结构和代谢变化,进行了胰岛和肝组织的组织学分析。主要发现:与CTL小鼠相比,给予他莫昔芬后KO小鼠的空腹血糖水平较低,表明葡萄糖调节的胰岛素分泌受损。hfd喂养的KO小鼠消耗较少的食物,但表现出更大的体重增加和肛周脂肪积累,反映出更高的能量效率。组织学分析显示,HFD组KO小鼠肝脏脂肪变性和纤维化更为明显。葡萄糖不耐受和胰岛素抵抗在KO小鼠中加剧,突出了它们无法适应增加的代谢需求。结构分析显示,KO小鼠未能表现出hfd诱导的β细胞团扩增,导致胰岛直径和数量减少,证实了HNF4α在β细胞适应中的关键作用。意义:本研究表明,在致肥环境下,HNF4α对胰腺β细胞的代谢和结构适应至关重要。缺乏HNF4α会损害β细胞功能,导致对葡萄糖耐受不良和胰岛素抵抗的易感性增加。这些发现强调了HNF4α在维持葡萄糖稳态中的重要性,并强调了其作为肥胖患者糖尿病管理的治疗靶点的潜力。
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来源期刊
Frontiers in Endocrinology
Frontiers in Endocrinology Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
5.70
自引率
9.60%
发文量
3023
审稿时长
14 weeks
期刊介绍: Frontiers in Endocrinology is a field journal of the "Frontiers in" journal series. In today’s world, endocrinology is becoming increasingly important as it underlies many of the challenges societies face - from obesity and diabetes to reproduction, population control and aging. Endocrinology covers a broad field from basic molecular and cellular communication through to clinical care and some of the most crucial public health issues. The journal, thus, welcomes outstanding contributions in any domain of endocrinology. Frontiers in Endocrinology publishes articles on the most outstanding discoveries across a wide research spectrum of Endocrinology. The mission of Frontiers in Endocrinology is to bring all relevant Endocrinology areas together on a single platform.
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