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?-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.

ABSTRACT: The presence of insulin receptor (IR) on ?-cells suggests that insulin has an autocrine/paracrine role in the regulation of ?-cell function. It has previously been reported that the ?-cell specific loss of IR (?IRKO) leads to the development of impaired glycemic regulation and ?-cell death in mice. However, temporally controlled ?IRKO induced during the distinct transitions of fetal pancreas development has yet to be investigated. We hypothesized that the presence of IR on ?-cells during the 2nd transition phase of the fetal murine pancreas is required for maintaining normal islet development.We utilized a mouse insulin 1 promoter driven tamoxifen-inducible Cre-recombinase IR knockout (MIP-?IRKO) mouse model to investigate the loss of ?-cell IR during pancreatic development at embryonic day (e) 13, a phase of endocrine proliferation and ?-cell fate determination. Fetal pancreata examined at e19-20 showed significantly reduced IR levels in the ?-cells of MIP-?IRKO mice. Morphologically, MIP-?IRKO pancreata exhibited significantly enlarged islet size with increased ?-cell area and proliferation. MIP-?IRKO pancreata also displayed significantly increased Igf-2 protein level and Akt activity with a reduction in phospho-p53 when compared to control littermates. Islet vascular formation and Vegf-a protein level was significantly increased in MIP-?IRKO pancreata.Our results demonstrate a developmental role for the ?-cell IR, whereby its loss leads to an islet compensatory overgrowth, and contributes further information towards elucidating the temporally sensitive signaling during ?-cell commitment.

SUBMITTER: Trinder M

PROVIDER: S-EPMC5216695 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.

Trinder Mark M Zhou Liangyi L Oakie Amanda A Riopel Matthew M Wang Rennian R

Oncotarget 20160701 29

The presence of insulin receptor (IR) on β-cells suggests that insulin has an autocrine/paracrine role in the regulation of β-cell function. It has previously been reported that the β-cell specific loss of IR (βIRKO) leads to the development of impaired glycemic regulation and β-cell death in mice. However, temporally controlled βIRKO induced during the distinct transitions of fetal pancreas development has yet to be investigated. We hypothesized that the presence of IR on β-cells during the 2nd ...[more]

PMID: 27384998

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Project description:Peroxisome proliferator-activated receptor β/δ (PPARβ/δ), the most PPAR abundant isotype in the central nervous system, is involved in microglial homeostasis and metabolism, whose disturbances have been demonstrated to play a key role in memory impairment. Although PPARβ/δ function is well-established in metabolism, its contribution to neuronal and specifically memory process is underexplored. Therefore, the aim of the study is to determine the role of PPARβ/δ in the neuropathological pathways involved in memory impairment and as to whether a risk factor implicated in memory loss such as obesity modulates neuropathological markers. To carry out this study, 6-month-old total knock-out for the Ppard gene male mice with C57BL/6X129/SV background (PPARβ/δ-/-) and wild-type (WT) littermates with the same genetic background were used. Animals were fed, after the weaning (at 21 days old), and throughout their growth, either conventional chow (CT) or a palmitic acid-enriched diet (HFD). Thus, four groups were defined: WT CT, WT HFD, PPARβ/δ-/- CT, and PPARβ/δ-/- HFD. Before sacrifice, novel object recognition test (NORT) and glucose and insulin tolerance tests were performed. After that, animals were sacrificed by intracardiac perfusion or cervical dislocation. Different techniques, such as GolgiStain kit or immunofluorescence, were used to evaluate the role of PPARβ/δ in memory dysfunction. Our results showed a decrease in dendritic spine density and synaptic markers in PPARβ/δ-/- mice, which were corroborated in the NORT. Likewise, our study demonstrated that the lack of PPARβ/δ receptor enhances gliosis in the hippocampus, contributing to astrocyte and microglial activation and to the increase in neuroinflammatory biomarkers. Additionally, alterations in the hippocampal insulin receptor pathway were found. Interestingly, while some of the disturbances caused by the lack of PPARβ/δ were not affected by feeding the HFD, others were exacerbated or required the combination of both factors. Taken together, the loss of PPARβ/δ-/- affects neuronal and synaptic structure, contributing to memory dysfunction, and they also present this receptor as a possible new target for the treatment of memory impairment.

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?-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.

Publications

β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.

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