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NCS-1 Deficiency Is Associated With Obesity and Diabetes Type 2 in Mice.

ABSTRACT: Neuronal calcium sensor-1 (NCS-1) knockout (KO) in mice (NCS-1^-/- mice) evokes behavioral phenotypes ranging from learning deficits to avolition and depressive-like behaviors. Here, we showed that with the onset of adulthood NCS-1^-/- mice gain considerable weight. Adult NCS-1^-/- mice are obese, especially when fed a high-fat diet (HFD), are hyperglycemic and hyperinsulinemic and thus develop a diabetes type 2 phenotype. In comparison to wild type (WT) NCS-1^-/- mice display a significant increase in adipose tissue mass. NCS-1^-/- adipocytes produce insufficient serum concentrations of resistin and adiponectin. In contrast to WT littermates, adipocytes of NCS-1^-/- mice are incapable of up-regulating insulin receptor (IR) concentration in response to HFD. Thus, HFD-fed NCS-1^-/- mice exhibit in comparison to WT littermates a significantly reduced IR expression, which may explain the pronounced insulin resistance observed especially with HFD-fed NCS-1^-/- mice. We observed a direct correlation between NCS-1 and IR concentrations in the adipocyte membrane and that NCS-1 can be co-immunoprecipitated with IR indicating a direct interplay between NCS-1 and IR. We propose that NCS-1 plays an important role in adipocyte function and that NCS-1 deficiency gives rise to obesity and diabetes type 2 in adult mice. Given the association of altered NCS-1 expression with behaviorial abnormalities, NCS-1^-/- mice may offer an interesting perspective for studying in a mouse model a potential genetic link between some psychiatric disorders and the risk of being obese.

SUBMITTER: Ratai O

PROVIDER: S-EPMC6456702 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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NCS-1 Deficiency Is Associated With Obesity and Diabetes Type 2 in Mice.

Ratai Olga O Hermainski Joanna J Ravichandran Keerthana K Pongs Olaf O

Frontiers in molecular neuroscience 20190403

Neuronal calcium sensor-1 (NCS-1) knockout (KO) in mice (NCS-1-/- mice) evokes behavioral phenotypes ranging from learning deficits to avolition and depressive-like behaviors. Here, we showed that with the onset of adulthood NCS-1-/- mice gain considerable weight. Adult NCS-1-/- mice are obese, especially when fed a high-fat diet (HFD), are hyperglycemic and hyperinsulinemic and thus develop a diabetes type 2 phenotype. In comparison to wild type (WT) NCS-1- ...[more]

PMID: 31001084

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Project description:Aims/hypothesisIgM is the primary antibody produced by B cells and we hypothesise that IgM antibodies to gut microbiota may play a role in immunometabolism in obesity and type 2 diabetes. To test our hypothesis, we used B6 mice deficient in activation-induced cytidine deaminase (Aid-/- [also known as Aicda-/-]) which secrete only IgM antibodies, and human faecal samples.MethodsWe studied the immunometabolic effects and gut microbial changes in high-fat-diet-induced obesity (HFDIO) in Aid-/- B6 mice compared with wild-type mice. To determine similarities between mice and humans, human stool samples were collected from children and adolescents who were obese with normal glucose tolerance (NGT), obese with glucose intolerance (IGT), or obese and newly diagnosed with type 2 diabetes, for faecal microbiota transplant (FMT) into germ-free (GF) B6 mice and we assessed IgM-bound bacteria and immune responses.ResultsCompared with wild-type mice, Aid-/- B6 mice developed exacerbated HFDIO due to abundant levels of IgM. FMT from Aid-/- B6 to GF B6 mice promoted greater weight gain in recipient mice compared with FMT using wild-type mouse faecal microbiota. Obese youth with type 2 diabetes had more IgM-bound gut bacteria. Using the stools from the obese youth with type 2 diabetes for FMT to GF B6 mice, we observed that the gut microbiota promoted body weight gain and impaired glucose tolerance in the recipient GF B6 mice. Importantly, some clinical features of these obese young individuals were mirrored in the GF B6 mice following FMT.Conclusions/interpretationOur results suggest that IgM-bound gut microbiota may play an important role in the immuno-pathogenesis of obesity and type 2 diabetes, and provide a novel link between IgM in obesity and type 2 diabetes in both mice and humans.Data availabilityThe 16s rRNA sequencing datasets supporting the current study have been deposited in the NCBI SRA public repository ( https://www.ncbi.nlm.nih.gov/sra ; accession no. SAMN18796639).

Dataset Information

NCS-1 Deficiency Is Associated With Obesity and Diabetes Type 2 in Mice.

Publications

NCS-1 Deficiency Is Associated With Obesity and Diabetes Type 2 in Mice.

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