Dataset Information

Acute Deletion of METTL14 in ?-Cells of Adult Mice Results in Glucose Intolerance.

ABSTRACT: N6-Methyladenosine (m6A) is the most common and abundant mRNA modification that involves regulating the RNA metabolism. However, the role of m6A in regulating the ?-cell function is unclear. Methyltransferase-like 14 (METTL14) is a key component of the m6A methyltransferase complex. To define the role of m6A in regulating the ?-cell function, we generated ?-cell METTL14-specific knockout (?KO) mice by tamoxifen administration. Acute deletion of Mettl14 in ?-cells results in glucose intolerance as a result of a reduction in insulin secretion in ?-cells even though ?-cell mass is increased, which is related to increased ?-cell proliferation. To define the molecular mechanism, we performed RNA sequencing to detect the gene expression in ?KO islets. The genes responsible for endoplasmic reticulum stress, such as Ire1?, were among the top upregulated genes. Both mRNA and protein levels of IRE1? and spliced X-box protein binding 1 (sXBP-1) were increased in ?KO islets. The protein levels of proinsulin and insulin were decreased in ?KO islets. These results suggest that acute METTL14 deficiency in ?-cells induces glucose intolerance by increasing the IRE1?/sXBP-1 pathway.

SUBMITTER: Men L

PROVIDER: S-EPMC6760293 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Acute Deletion of METTL14 in β-Cells of Adult Mice Results in Glucose Intolerance.

Men Lili L Sun Juan J Luo Guanzheng G Ren Decheng D

Endocrinology 20191001 10

N6-Methyladenosine (m6A) is the most common and abundant mRNA modification that involves regulating the RNA metabolism. However, the role of m6A in regulating the β-cell function is unclear. Methyltransferase-like 14 (METTL14) is a key component of the m6A methyltransferase complex. To define the role of m6A in regulating the β-cell function, we generated β-cell METTL14-specific knockout (βKO) mice by tamoxifen administration. Acute deletion of Mettl14 in β-cells results in glucose intolerance a ...[more]

PMID: 31369074

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Project description:BACKGROUND:The cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and ?-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of ?-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in ?-cells. METHODS:Mice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in ?-cells (? GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. ?-cell size and number were measured by immunofluorescence-based islet morphometry. RESULTS:In vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from ? GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in ? GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in ?-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and ?-cell morphology were similar in ? GC-A KO mice and control littermates. However, HFD-fed ? GC-A KO animals had accelerated glucose intolerance and diminished adaptative ?-cell proliferation. CONCLUSIONS:Our studies of ? GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate ?-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of ?-cells to HFD-induced obesity. Impaired ?-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.

Dataset Information

Acute Deletion of METTL14 in ?-Cells of Adult Mice Results in Glucose Intolerance.

Publications

Acute Deletion of METTL14 in β-Cells of Adult Mice Results in Glucose Intolerance.

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