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

Abstract

Abstract3-Hydroxybutyrate (3HB) is a small ketone body molecule produced endogenously by the body in the liver. Previous studies have shown that 3HB can reduce blood glucose level in type 2 diabetic (T2D) patients. However, there is no systematic study and clear mechanism to evaluate and explain the hypoglycemic effect of 3HB. Here we demonstrate that 3HB reduces fasting blood glucose level, improves glucose tolerance, and ameliorates insulin resistance in type 2 diabetic mice through hydroxycarboxylic acid receptor 2 (HCAR2). Mechanistically, 3HB increases intracellular calcium ion (Ca2+) levels by activating HCAR2, thereby stimulating adenylate cyclase (AC) to increase cyclic adenosine monophosphate (cAMP) concentration, and then activating protein kinase A (PKA). Activated PKA inhibits Raf1 proto-oncogene serine/threonine-protein kinase (Raf1) activity, resulting in a decrease in extracellular signal-regulated kinases 1/2 (ERK1/2) activity and ultimately inhibiting peroxisome proliferator-activated receptor γ (PPARγ) Ser273 phosphorylation in adipocytes. Inhibition of PPARγ Ser273 phosphorylation by 3HB altered the expression of PPARγ regulated genes and reduced insulin resistance. Collectively, 3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of HCAR2/Ca2+/cAMP/PKA/Raf1/ERK1/2/PPARγ.

Ketone body 3-hydroxybutyrate alleviates CCl4-induced liver fibrosis in mice through regulation of mitochondrial fission and reduction of oxidative stress

“…Previously, we found that 3HB had a protective effect on the liver of mice with type 2 diabetes[16]. CCl 4 directly causes liver cell injury, necrosis and inflammation, and is widely used in the establishment of animal models of liver fibrosis and cirrhosis[18].…”

“…Previously, we found that 3HB had a protective effect on the liver of mice with type 2 diabetes [16].…”

“…Previous reports have shown that 3HB can improve alcoholic liver injury and alleviate symptoms of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetic mice, demonstrating its protective effects on the liver [16,17]. Liver fibrosis is a common pathological consequence of both alcoholic liver injury and NAFLD [21].…”

“…Also, deficiency of 3HB dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting, which is the former step of liver fibrosis[15]. According to our previous study, 1,3-BDO, a precursor substance of 3HB, could reduce liver and kidney injury caused by type 2 diabetes, and improve liver function[16]. It was also reported that 3HB protects from alcohol-induced liver injury through a Hcar2-cAMP dependent pathway [17].…”

Characterizing the metabolic divide: distinctive metabolites differentiating CAD-T2DM from CAD patients

“…Further studies are needed to gain a deeper understanding of these differences. 3-Hydroxybutyrate, originating from the increased β-oxidation of free fatty acids [ 40 ], is found in higher concentrations in the plasma of T2DM patients [ 41 ] and has been shown to ameliorate insulin resistance in T2DM mice through the HCAR2/Ca 2+ /cAMP/PKA/Raf1/ERK1/2/PPARγ pathway [ 42 ].…”