Cover Story Current Issue

Weaning involves a dietary switch in mammals, progressively decreasing the reliance on the consumption of a fat-rich milk diet in favour of a carbohydrate-rich diet. Metabolic adaptation to this shift in macronutrient consumption is characterized by reduced hepatic gluconeogenesis, increased liver glycogen content, and changes in lipid metabolism. Such metabolic changes are supported by various nutritional, hormonal, and neuronal factors. Dietary changes during weaning are shown to drive β-cell proliferation and maturation, which is important for the optimal endocrine function of the pancreas. A switch from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5′-adenosine monophosphate-activated protein kinase (AMPK) was found critical for functional maturation of β-cells. Furthermore, changes in the macronutrient composition during the weaning process drive alterations in the gut microbiome, which is essential for the development of immune tolerance. The major calcium absorption pathway also changes during weaning, from the paracellular pathway during the suckling stage to the vitamin D dependent transcellular pathway post-weaning. However, the factors that regulate these post-weaning metabolic adaptations are not fully understood.

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Current Issue

Whole body and hematopoietic cell-specific deletion of G-protein coupled receptor 65 (GPR65) improves insulin sensitivity in diet-induced obese mice

Yingjiang Zhou, EunJu Bae, Simon S. Hoffman, Da Young Oh, ... Saswata Talukdar

Whole body and hematopoietic cell-specific deletion of G-protein coupled receptor 65 (GPR65) improves insulin sensitivity in diet-induced obese mice

 

Objective

Acidic extracellular microenvironments, resulting from enhanced glycolysis and lactic acid secretion by immune cells, along with metabolic acidosis may interfere with the insulin signaling pathway and contribute to the development of insulin resistance. In the present study, we investigated the role of G protein-coupled receptor GPR65, an extracellular pH sensing protein, in modulating insulin resistance.

Methods

We measured GPR65 expression in the adipose tissue (AT) of subjects with varying metabolic health states. We utilized whole-body and hematopoietic cell-specific GPR65 knockout (KO) mice to investigate the mechanism underlying the associations between GPR65, inflammatory response, and insulin resistance.

Results

Elevated GPR65 expression was observed in the AT of subjects with obesity, compared to their lean counterparts, and was inversely correlated with insulin resistance. In GPR65 KO mice, improved insulin sensitivity and decreased hepatic lipid content were observed, attributed to concomitant increases in mitochondrial activity and fatty acid β-oxidation in liver. GPR65 KO mice also exhibited increased Akt phosphorylation in skeletal muscle, suppressed proinflammatory gene expression in AT, and decreased serum cytokine levels, collectively suggesting the anti-inflammatory effects of GPR65 depletion. This was further confirmed by observations of decreased macrophage chemotaxis towards AT in vitro, and depressed inflammatory signaling pathway activation in bone marrow-derived dendritic cells from GPR65 KO mice. Additionally, hematopoietic lineage-specific GPR65 KO mice exhibited improved whole body insulin sensitivity in clamp studies, demonstrating GPR65 signaling in immune cells mediates this effect.

Conclusions

Our data suggests that macrophage-specific GPR65 signaling contributes to inflammation and the development of insulin resistance.

 

Articles in Press

Whole body and hematopoietic cell-specific deletion of G-protein coupled receptor 65 (GPR65) improves insulin sensitivity in diet-induced obese mice

Yingjiang Zhou, EunJu Bae, Simon S. Hoffman, Da Young Oh, ... Saswata Talukdar

Whole body and hematopoietic cell-specific deletion of G-protein coupled receptor 65 (GPR65) improves insulin sensitivity in diet-induced obese mice

 

Objective

Acidic extracellular microenvironments, resulting from enhanced glycolysis and lactic acid secretion by immune cells, along with metabolic acidosis may interfere with the insulin signaling pathway and contribute to the development of insulin resistance. In the present study, we investigated the role of G protein-coupled receptor GPR65, an extracellular pH sensing protein, in modulating insulin resistance.

Methods

We measured GPR65 expression in the adipose tissue (AT) of subjects with varying metabolic health states. We utilized whole-body and hematopoietic cell-specific GPR65 knockout (KO) mice to investigate the mechanism underlying the associations between GPR65, inflammatory response, and insulin resistance.

Results

Elevated GPR65 expression was observed in the AT of subjects with obesity, compared to their lean counterparts, and was inversely correlated with insulin resistance. In GPR65 KO mice, improved insulin sensitivity and decreased hepatic lipid content were observed, attributed to concomitant increases in mitochondrial activity and fatty acid β-oxidation in liver. GPR65 KO mice also exhibited increased Akt phosphorylation in skeletal muscle, suppressed proinflammatory gene expression in AT, and decreased serum cytokine levels, collectively suggesting the anti-inflammatory effects of GPR65 depletion. This was further confirmed by observations of decreased macrophage chemotaxis towards AT in vitro, and depressed inflammatory signaling pathway activation in bone marrow-derived dendritic cells from GPR65 KO mice. Additionally, hematopoietic lineage-specific GPR65 KO mice exhibited improved whole body insulin sensitivity in clamp studies, demonstrating GPR65 signaling in immune cells mediates this effect.

Conclusions

Our data suggests that macrophage-specific GPR65 signaling contributes to inflammation and the development of insulin resistance.

 

Save the Date

12th Helmholtz 
Diabetes Conference 
22-24. Sep, Munich

2022 impact factor: 6.6

You are what you eat

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