Feb 1, 2025

Feb 1, 2025

Feb 1, 2025

3‑Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice

3‑Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice

3‑Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice

3‑Hydroxybutyrate (3HB) is one of the main ketone bodies produced by the liver during fasting or ketogenic diets. In a study using genetically diabetic mice, researchers evaluated whether increasing circulating 3HB could improve glycaemic control. They found that oral supplementation of a 3HB precursor lowered fasting blood glucose, improved glucose tolerance and reduced insulin resistance. Mechanistically, 3HB acted through the hydroxycarboxylic acid receptor 2 (HCAR2) to raise intracellular Ca2+ and cyclic AMP (cAMP) levels, activating protein kinase A and ultimately inhibiting phosphorylation of the nuclear receptor PPARγ at Ser273—a modification linked with insulin resistance. Genes downstream of PPARγ showed improved expression, and treated mice showed lower HOMA‑IR scores and improved metabolic profiles. These findings suggest that elevating circulating 3HB may be a practical strategy for improving insulin sensitivity in type 2 diabetes.

3‑Hydroxybutyrate (3HB) is one of the main ketone bodies produced by the liver during fasting or ketogenic diets. In a study using genetically diabetic mice, researchers evaluated whether increasing circulating 3HB could improve glycaemic control. They found that oral supplementation of a 3HB precursor lowered fasting blood glucose, improved glucose tolerance and reduced insulin resistance. Mechanistically, 3HB acted through the hydroxycarboxylic acid receptor 2 (HCAR2) to raise intracellular Ca2+ and cyclic AMP (cAMP) levels, activating protein kinase A and ultimately inhibiting phosphorylation of the nuclear receptor PPARγ at Ser273—a modification linked with insulin resistance. Genes downstream of PPARγ showed improved expression, and treated mice showed lower HOMA‑IR scores and improved metabolic profiles. These findings suggest that elevating circulating 3HB may be a practical strategy for improving insulin sensitivity in type 2 diabetes.

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Summary of

3‑Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice

By

Yudian Zhang

Yudian Zhang

, et al.

, et al.

View Study PDF

Purpose Type 2 diabetes (T2D) is characterized by chronic hyperglycaemia and insulin resistance. Some clinical observations suggest that elevated β‑hydroxybutyrate (3HB) reduces blood glucose in T2D patients, but the mechanism is unclear. This study aimed to determine whether increasing 3HB ameliorates insulin resistance in diabetic mice and to elucidate the molecular pathway involved. Methods Researchers used db/db mice (a model of T2D) and streptozotocin‑treated mice to induce chronic hyperglycaemia. Mice were fed diets supplemented with 1,3‑butanediol (1,3‑BDO), a 3HB precursor that is metabolized to 3HB in the liver. Fasting blood glucose, glucose tolerance (ipGTT), insulin tolerance (ipITT) and HOMA‑IR indices were measured over several weeks. Adipocytes were isolated to examine phosphorylation of peroxisome proliferator‑activated receptor γ (PPARγ) at Ser273 and expression of downstream genes. Mechanistic studies assessed HCAR2‑dependent signalling, intracellular Ca2+, cAMP levels, protein kinase A (PKA) activity, and Raf1/ERK1/2 pathway activation. Results Supplementation with 1,3‑BDO increased circulating 3HB concentrations in diabetic mice and significantly lowered fasting blood glucose compared with vehicle‑treated controls. Treated mice displayed improved glucose tolerance and decreased HOMA‑IR values, indicating better insulin sensitivity. Mechanistic experiments showed that 3HB bound to HCAR2, increasing intracellular Ca2+ and cAMP, which activated PKA. PKA activity inhibited Raf1 and ERK1/2 signalling, reducing phosphorylation of PPARγ at Ser273. Reduced Ser273 phosphorylation normalized expression of PPARγ target genes involved in adipocyte insulin signalling and lipid metabolism. In vitro, knockdown of HCAR2 blocked the metabolic benefits of 3HB, confirming receptor dependence. Conclusion

Elevating circulating 3HB improves glycaemic control and insulin sensitivity in murine models of T2D by activating the HCAR2–Ca2+/cAMP/PKA pathway and inhibiting PPARγ Ser273 phosphorylation. These findings suggest that ketone elevation—via supplementation or ketogenic diets—could be explored as a therapeutic strategy for T2D. Future clinical studies are needed to evaluate whether controlled 3HB elevation safely improves insulin sensitivity in humans and whether combining ketone supplementation with existing antidiabetic agents provides synergistic benefits.

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