Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation
Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.
The antianginal ranolazine mitigates obesity-induced nonalcoholic fatty liver disease and increases hepatic pyruvate dehydrogenase activity
Obese individuals are often at risk for nonalcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes (T2D), and cardiovascular diseases such as angina, thereby requiring combination therapies for their comorbidities. Ranolazine is a second-line antianginal agent that also improves glycemia, and our aim was to determine whether ranolazine modifies the progression of obesity-induced NAFLD. Twelve-week-old C57BL/6J male mice were fed a low-fat or high-fat diet for 10 weeks and then treated for 30 days with either vehicle control or ranolazine (50 mg/kg via daily s.c. injection). Glycemia was monitored via glucose/pyruvate/insulin tolerance testing, whereas in vivo metabolism was assessed via indirect calorimetry. Hepatic triacylglycerol content was quantified via the Bligh and Dyer method. Consistent with previous reports, ranolazine treatment reversed obesity-induced glucose intolerance, which was associated with reduced body weight and hepatic steatosis, as well as increased hepatic pyruvate dehydrogenase (PDH) activity. Ranolazine's actions on hepatic PDH activity may be directly mediated, as ranolazine treatment reduced PDH phosphorylation (indicative of increased PDH activity) in HepG2 cells. Therefore, in addition to mitigating angina, ranolazine also reverses NAFLD, which may contribute to its documented glucose-lowering actions, situating ranolazine as an ideal antianginal therapy for obese patients comorbid for NAFLD and T2D.
Skeletal muscle-specific Cre recombinase expression, controlled by the human α-skeletal actin promoter, improves glucose tolerance in mice fed a high-fat diet
Cre-loxP systems are frequently used in mouse genetics as research tools for studying tissue-specific functions of numerous genes/proteins. However, the expression of Cre recombinase in a tissue-specific manner often produces undesirable changes in mouse biology that can confound data interpretation when using these tools to generate tissue-specific gene knockout mice. Our objective was to characterise the actions of Cre recombinase in skeletal muscle, and we anticipated that skeletal muscle-specific Cre recombinase expression driven by the human α-skeletal actin (HSA) promoter would influence glucose homeostasis.
Glucagon-like peptide-1 receptor mediated control of cardiac energy metabolism
Glucagon-like peptide-1 receptor (GLP-1R) agonists are frequently used to improve glycemia in patients with type 2 diabetes (T2D). Recent data from cardiovascular outcomes trials for the GLP-1R agonists, liraglutide and semaglutide, have also demonstrated significant reductions in death rates from cardiovascular causes in patients with T2D. As cardiovascular death is the number one cause of death in patients with T2D, understanding the mechanisms by which GLP-1R agonists such as liraglutide and semaglutide improve cardiac function is essential. Yet despite strong evidence from preclinical and clinical studies supporting the cardioprotective actions of GLP-1R agonists, the precise mechanism(s) by which this drug-class for T2D may produce these beneficial actions remains enigmatic. Negligible GLP-1R expression in ventricular cardiac myocytes suggests that GLP-1R agonist-induced cardioprotection is likely partially attributed to indirect actions on peripheral tissues other than the heart. Because insulin increases glucose oxidation, whereas glucagon increases fatty acid oxidation in the heart, GLP-1R agonist-induced increases and decreases in insulin and glucagon secretion, respectively, may modify cardiac energy metabolism in T2D patients. This may represent a potential mechanism for GLP-1R agonist-induced cardioprotection in T2D, as increases in fatty acid oxidation and decreases in glucose oxidation are frequently observed in the hearts of animals and human subjects with T2D.