Hepatocyte Nuclear Factor 4-alpha (HNF4 alpha) controls the insulin resistance-induced pancreatic beta-cell mass expansion

Autor(es)

Barth, Robson ^{[1, 2]} ; Ruoso, Carolina ^{[1, 2]} ; Ferreira, Sandra Mara ^[3] ; de Ramos, Francieli Caroline ^{[1, 2]} ; Lima, Fernanda Barbosa ^{[1, 2]} ; Boschero, Antonio Carlos ^[3] ; dos Santos, Gustavo Jorge ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Fed Univ Santa Catarina UFSC, Ctr Biol Sci, Dept Physiol Sci, Islet Biol & Metab Lab IBM Lab, BR-88040900 Florianopolis, SC - Brazil

^[2] Fed Univ Santa Catarina UFSC, Multictr Grad Program Physiol Sci, BR-88040900 Florianopolis, SC - Brazil

^[3] State Univ Carnpinas, Inst Biol, Dept Struct & Funct Biol, Lab Endocrine Pancreas & Metab LAPEM, UNICAMP, BR-13083862 Campinas - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Life Sciences; v. 289, JAN 15 2022.
• Citações Web of Science: 0

Resumo

Background: Regardless of the etiology, any type of DM presents a reduction of insulin-secreting cell mass, so it is important to investigate pathways that induce the increase of this cell mass. Aim: Based on the fact that (1) HNF4 alpha is crucial for beta-cell proliferation, (2) DEX-induced IR promotes beta-cell mass expansion, and (3) the stimulation of beta-cell mass expansion may be an important target for DM therapies, we aimed to investigate whether DEX-induced proliferation of beta pancreatic cells is dependent on HNF4 alpha. Methods: We used WildType (WT) and Knockout (KO) mice for HNF4-alpha, treated or not with 100 mg/Kg/day of DEX, for 5 consecutive days. One day after the last injection of DEX the IR was confirmed by ipITT and the mice were euthanized for pancreas removal. Results: In comparison to WT, KO mice presented increased glucose tolerance, lower fasting glucose and increased glucose-stimulates insulin secretion (GSIS). DEX induced IR in both KO and WT mice. In addition, DEX-induced beta-cell mass expansion and an increase in the Ki67 immunostaining were observed only in WT mice, evidencing that IR-induced beta-cell mass expansion is dependent on HNF4 alpha. Also, we observed that DEX-treatment, in an HNF4 alpha-dependent way, promoted an increase in PDX1, PAX4 and NGN3 gene expression. Conclusions: Our results strongly suggest that DEX-induced IR promotes beta-cell mass expansion through processes of proliferation and neogenesis that depend on the HNF4 alpha activity, pointing to HNF4 alpha as a possible therapeutic target in DM treatment. (AU)

• Processo FAPESP: 15/12611-0 - Mecanismos moleculares envolvidos na disfunção e morte de células beta pancreáticas no Diabetes mellitus: estratégias para a inibição desses processos e para a recuperação da massa insular
• Beneficiário: Antonio Carlos Boschiero
• Modalidade de apoio: Auxílio à Pesquisa - Temático