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1.
Am J Physiol Endocrinol Metab ; 318(4): E579-E585, 2020 04 01.
Article in English | MEDLINE | ID: mdl-32101030

ABSTRACT

Defining the host receptors and metabolic consequences of bacterial components can help explain how the microbiome influences metabolic diseases. Bacterial peptidoglycans that activate nucleotide-binding oligomerization domain-containing (NOD)1 worsen glucose control, whereas NOD2 activation improves glycemia. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is required for innate immunity instigated by NOD1 and NOD2. The role of RIPK2 in the divergent effects of NOD1 versus NOD2 on blood glucose was unknown. We found that whole body deletion of RIPK2 negated all effects of NOD1 or NOD2 activation on blood glucose during an acute, low level endotoxin challenge in mice. It was known that NOD1 in hematopoietic cells participates in insulin resistance and metabolic inflammation in obese mice. It was unknown if RIPK2 in hematopoietic cells is required for the glucose-lowering and anti-inflammatory effects of NOD2 activation. We hypothesized that RIPK2 in nonhematopoietic cells dictated the glycemic effects of NOD2 activation. We found that whole body deletion of RIPK2 prevented the glucose-lowering effects of repeated NOD2 activation that were evident during a glucose tolerance test (GTT) in high-fat diet (HFD)-fed wild-type (WT) mice. NOD2 activation lowered glucose during a GTT and lowered adipose tissue inflammation in mice with RIPK2 deleted in hematopoietic cells. We conclude that RIPK2 in nonhematopoietic cells mediates the glucose lowering and anti-inflammatory effects of NOD2-activating postbiotics. We propose a model where lipopolysaccharides and NOD1 ligands synergize in hematopoietic cells to promote insulin resistance but NOD2 activation in nonhematopoietic cells promotes RIPK2-dependent immune tolerance and lowering of inflammation and insulin resistance.


Subject(s)
Blood Glucose/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Microbiota , Nod2 Signaling Adaptor Protein/metabolism , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Activation, Metabolic , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Diet, High-Fat , Glucose Tolerance Test , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Nod1 Signaling Adaptor Protein/metabolism , Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics
2.
Diabetes ; 67(7): 1285-1296, 2018 07.
Article in English | MEDLINE | ID: mdl-29496744

ABSTRACT

The current demographic shift toward an aging population has led to a robust increase in the prevalence of age-associated metabolic disorders. Recent studies have demonstrated that the etiology of obesity-related insulin resistance that develops with aging differs from that induced by high-calorie diets. Whereas the role of adaptive immunity in changes in energy metabolism driven by nutritional challenges has recently gained attention, its impact on aging remains mostly unknown. Here we found that the number of follicular B2 lymphocytes and expression of the B-cell-specific transcriptional coactivator OcaB increase with age in spleen and in intra-abdominal epididymal white adipose tissue (eWAT), concomitantly with higher circulating levels of IgG and impaired glucose homeostasis. Reduction of B-cell maturation and Ig production-especially that of IgG2c-by ablation of OcaB prevented age-induced glucose intolerance and insulin resistance and promoted energy expenditure by stimulating fatty acid utilization in eWAT and brown adipose tissue. Transfer of wild-type bone marrow in OcaB-/- mice replenished the eWAT B2-cell population and IgG levels, which diminished glucose tolerance, insulin sensitivity, and energy expenditure while increasing body weight gain in aged mice. Thus these findings demonstrate that upon aging, modifications in B-cell-driven adaptive immunity contribute to glucose intolerance and fat accretion.


Subject(s)
Aging/metabolism , B-Lymphocytes/physiology , Energy Metabolism/genetics , Insulin Resistance/genetics , Lipid Metabolism/genetics , Obesity , Trans-Activators/genetics , Adolescent , Adult , Aged , Aging/genetics , Animals , Cell Differentiation/genetics , Cell Differentiation/immunology , Cells, Cultured , Epididymis , Female , Glucose Intolerance/genetics , Glucose Intolerance/immunology , Glucose Intolerance/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Obesity/complications , Obesity/genetics , Obesity/immunology , Obesity/metabolism , Young Adult
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