long_term_HFD_SENP1_V11_Supplemental.pdf (25.64 MB)
Download fileβ-cell knockout of SENP1 reduces responses to incretins and worsens oral glucose tolerance in high fat diet-fed mice
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posted on 2021-08-30, 03:33 authored by Haopeng Lin, Nancy Smith, Aliya F Spigelman, Kunimasa Suzuki, Mourad Ferdaoussi, Tamadher A. Alghamdi, Sophie L Lewandowski, Yaxing Jin, Austin Bautista, Ying Wayne Wang, Jocelyn E. Manning Fox, Matthew J Merrins, Jean Buteau, Patrick E MacDonaldSUMOylation reduces
oxidative stress and preserves islet mass at the expense of robust insulin
secretion. To investigate a role for the deSUMOylating enzyme sentrin-specific
protease 1 (SENP1) following metabolic stress, we put
pancreas/gut-specific SENP1 knockout mice (pSENP1-KO) on a high fat diet (HFD).
Male pSENP1-KO mice were more glucose intolerant following HFD than littermate
controls, but only in response to oral glucose. A similar phenotype was
observed in females. Plasma glucose-dependent insulinotropic polypeptide (GIP)
and glucagon-like-peptide 1 (GLP-1) responses were identical in pSENP1-KO and
-WT littermates, including the HFD-induced upregulation of GIP responses. Islet
mass was not different, but insulin secretion and β-cell exocytotic responses
to the GLP-1 receptor agonist Exendin-4 (Ex4) and GIP were impaired in islets
lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, so we
generated β-cell-specific SENP1 knockout mice (βSENP1-KO). These phenocopied
the pSENP1-KO mice with selective impairment in oral glucose tolerance
following HFD, preserved islet mass expansion, and impaired β-cell exocytosis
and insulin secretion to Ex4 and GIP without changes in cAMP or Ca2+
levels. Thus, β-cell SENP1 limits oral glucose intolerance following HFD by
ensuring robust insulin secretion at a point downstream of incretin signaling.