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1.
Nat Commun ; 12(1): 1680, 2021 03 15.
Article in English | MEDLINE | ID: mdl-33723250

ABSTRACT

Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reamination to valine. Activation of cardiac branched-chain α-ketoacid dehydrogenase (BCKDH) by treatment with the BCKDH kinase inhibitor, BT2, does not impede the strong flux of [U-13C]KIV to valine. Sequestration of BCAA and BCKA away from mitochondrial oxidation is likely due to low levels of expression of the mitochondrial BCAA transporter SLC25A44 in the heart, as its overexpression significantly lowers accumulation of [13C]-labeled valine from [U-13C]KIV. Finally, exposure of perfused hearts to levels of BCKA found in obese rats increases phosphorylation of the translational repressor 4E-BP1 as well as multiple proteins in the MEK-ERK pathway, leading to a doubling of total protein synthesis. These data suggest that elevated BCKA levels found in obesity may contribute to pathologic cardiac hypertrophy via chronic activation of protein synthesis.


Subject(s)
Amino Acids, Branched-Chain/metabolism , Heart/physiology , Hemiterpenes/metabolism , Keto Acids/metabolism , Animals , Male , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Obesity/metabolism , Rats , Valine/metabolism
2.
EBioMedicine ; 27: 200-213, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29290411

ABSTRACT

Prescription ω-3 fatty acid ethyl ester supplements are commonly used for the treatment of hypertriglyceridemia. However, the metabolic profile and effect of the metabolites formed by these treatments remain unknown. Here we utilized unbiased metabolomics to identify 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) as a significant metabolite of the ω-3-acid ethyl ester prescription Lovaza™ in humans. Administration of CMPF to mice before or after high-fat diet feeding at exposures equivalent to those observed in humans increased whole-body lipid metabolism, improved insulin sensitivity, increased beta-oxidation, reduced lipogenic gene expression, and ameliorated steatosis. Mechanistically, we find that CMPF acutely inhibits ACC activity, and induces long-term loss of SREBP1c and ACC1/2 expression. This corresponds to an induction of FGF21, which is required for long-term steatosis protection, as FGF21KO mice are refractory to the improved metabolic effects. Thus, CMPF treatment in mice parallels the effects of human Lovaza™ supplementation, revealing that CMPF may contribute to the improved metabolic effects observed with ω-3 fatty acid prescriptions.


Subject(s)
Dietary Supplements , Esters/therapeutic use , Fatty Acids, Omega-3/therapeutic use , Fatty Liver/drug therapy , Fatty Liver/prevention & control , Furans/therapeutic use , Metabolome , Propionates/therapeutic use , Adult , Animals , Diet, High-Fat , Dose-Response Relationship, Drug , Fatty Liver/metabolism , Fatty Liver/pathology , Female , Fibroblast Growth Factors/deficiency , Fibroblast Growth Factors/metabolism , Furans/metabolism , Humans , Insulin Resistance , Lipid Metabolism , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Knockout , Mice, Obese , Propionates/metabolism
3.
Aust J Prim Health ; 23(4): 329-334, 2017 09.
Article in English | MEDLINE | ID: mdl-28449728

ABSTRACT

Young Aboriginal fathers face social and emotional challenges in the transition to fatherhood, yet culturally appropriate support mechanisms are lacking. Peer mentoring to develop online- and mobile phone-based resources and support may be a viable approach to successfully engage these young men. This feasibility study engaged two trusted Aboriginal mentors and researchers to partner with one regional and two rural Aboriginal communities in New South Wales, Australia. Early in the research process, 20 young Aboriginal fathers were recruited as co-investigators. These fathers were integral in the development of web-based resources and testing of mobile phone-based text messaging and mood-tracking programs tailored to provide fathering and mental health support. Overwhelmingly positive feedback from evaluations reinforced community pride in and ownership of the outcomes. The young men's involvement was instrumental in not only developing culturally appropriate support, but also in building their capacity as role models for other fathers in the community. The positive results from this feasibility study support the adoption of participatory approaches in the development of resources for Aboriginal communities.


Subject(s)
Fathers/psychology , Native Hawaiian or Other Pacific Islander/psychology , Social Support , Cell Phone , Cultural Competency , Fathers/statistics & numerical data , Feasibility Studies , Humans , Internet , Male , New South Wales
4.
J Med Chem ; 60(5): 1860-1875, 2017 03 09.
Article in English | MEDLINE | ID: mdl-28171722

ABSTRACT

CMPF (2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid) is a metabolite that circulates at high concentrations in type 2 and gestational diabetes patients. Further, human clinical studies suggest it might have a causal role in these diseases. CMPF inhibits insulin secretion in mouse and human islets in vitro and in vivo in rodents. However, the metabolic fate of CMPF and the relationship of structure to effects on insulin secretion have not been significantly studied. The syntheses of CMPF and analogues are described. These include isotopically labeled molecules. Study of these materials in vivo has led to the first observation of a metabolite of CMPF. In addition, a wide range of CMPF analogues have been prepared and characterized in insulin secretion assays using both mouse and human islets. Several molecules that influence insulin secretion in vitro were identified. The molecules described should serve as interesting probes to further study the biology of CMPF.


Subject(s)
Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Furans/chemical synthesis , Furans/pharmacology , Insulin/metabolism , Animals , Cytochrome P-450 Enzyme System/metabolism , Humans , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/enzymology , Islets of Langerhans/metabolism , Mice
5.
Endocr Metab Immune Disord Drug Targets ; 12(2): 197-206, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22385114

ABSTRACT

Glycerolipid acyltransfereases play important roles in physiological and pathophysiological processes of triglyceride (TAG) metabolism and energy balance. Glycerol-3-phosphate acyltransferases (GPATs) are key enzymes in the triglyceride biosynthetic pathway. In addition to the mitochondrial GPAT1 that was first cloned and studied, novel microsomal enzyme isoforms have been discovered in recent years. The potential function of one of the GPATs, GPAT4, was studied in GPAT4 deficient mice that suggested its role in TAG synthesis in multiple tissues. Monoacylglycerol and diacylglycerol acyltransferases (MGAT2 and DGAT1) are important enzymes involved in intestinal triglyceride absorption, and studies in recent years from knockout mice have revealed their important role in whole body energy metabolism through changes in intestinal TAG absorption kinetics. Both MGAT2 and DGAT1 mice are resistant to dietinduced obesity and have improved insulin sensitivity and hepatic TAG accumulation. These data suggest that these enzymes are intimately involved in TAG metabolism and whole body energy homeostasis and that inhibition of these enzymes may provide therapeutic benefits for metabolic disorders such as obesity, metabolic syndrome, and type 2 diabetes.


Subject(s)
Energy Metabolism/physiology , Glycerol-3-Phosphate O-Acyltransferase/antagonists & inhibitors , Glycolipids/metabolism , Homeostasis/physiology , Molecular Targeted Therapy , Triglycerides/metabolism , Acyl Coenzyme A/metabolism , Animals , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Diacylglycerol O-Acyltransferase/metabolism , Enzyme Inhibitors/therapeutic use , Female , Glycerol-3-Phosphate O-Acyltransferase/metabolism , Humans , Intestinal Absorption/drug effects , Intestinal Absorption/physiology , Male , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Rats
6.
FASEB J ; 24(4): 1151-9, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19917675

ABSTRACT

General opioid receptor antagonists reduce food intake and body weight in rodents, but the contributions of specific receptor subtypes are unknown. We examined whether genetic deletion of the kappa-opioid receptor (KOR) in mice alters metabolic physiology. KOR-knockout (KO) and wild-type (WT) mice were fed a high-energy diet (HED) for 16 wk. KO mice had 28% lower body weight and 45% lower fat mass when compared to WT mice fed an HED. No differences in caloric intake were found. An HED reduced energy expenditure in WT mice, but not in KO mice. KOR deficiency led to an attenuation of triglyceride synthesis in the liver. Malonyl CoA levels were also reduced in response to an HED, thereby promoting hepatic beta-oxidation. Glycemic control was also found to be improved in KO mice. These data suggest a key role for KORs in the central nervous system regulation of the metabolic adaptation to an HED, as we were unable to detect expression of KOR in liver, white adipose tissue, or skeletal muscle in WT mice. This study provides the first evidence that KORs play an essential physiological role in the control of hepatic lipid metabolism, and KOR activation is a permissive signal toward fat storage.-Czyzyk, T. A., Nogueiras, R., Lockwood, J. F., McKinzie, J. H., Coskun, T., Pintar, J. E., Hammond, C., Tschöp, M. H., Statnick, M. A. kappa-Opioid receptors control the metabolic response to a high-energy diet in mice.


Subject(s)
Energy Intake , Liver/metabolism , Receptors, Opioid, kappa/metabolism , Triglycerides/biosynthesis , Adipose Tissue, White/metabolism , Animals , Body Weight/genetics , Gene Expression Regulation/genetics , Mice , Mice, Knockout , Muscle, Skeletal/metabolism , Organ Specificity/genetics , Oxidation-Reduction , Receptors, Opioid, kappa/genetics
7.
J Clin Invest ; 117(11): 3475-88, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17885689

ABSTRACT

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.


Subject(s)
Central Nervous System/metabolism , Lipid Metabolism , Melanocortins/metabolism , Signal Transduction/physiology , Adipocytes/cytology , Adipocytes/metabolism , Adipose Tissue/cytology , Adipose Tissue/metabolism , Animals , Behavior, Animal/physiology , Eating , Glucose/metabolism , Humans , Insulin/metabolism , Melanocyte-Stimulating Hormones/administration & dosage , Melanocyte-Stimulating Hormones/metabolism , Mice , Mice, Knockout , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Receptors, Melanocortin , alpha-MSH/administration & dosage , alpha-MSH/analogs & derivatives , alpha-MSH/metabolism
8.
J Pharmacol Exp Ther ; 312(1): 127-33, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15356215

ABSTRACT

Carnitine palmitoyltransferase 1beta (CPT-1beta) is a key regulator of the beta oxidation of long-chain fatty acids in skeletal muscle and therefore a potential therapeutic target for diseases associated with defects in lipid metabolism such as obesity and type 2 diabetes. C75 [4-methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid] is an alpha-methylene-butyrolactone that has been characterized as both an inhibitor of fatty acid synthase and more recently, an activator of CPT-1 (Thupari et al., 2002). Using human CPT-1beta expressed in the yeast Pichia pastoris, we demonstrate that C75 can activate the skeletal muscle isoform of CPT-1 and overcome inactivation of the enzyme by malonyl CoA, an important physiological repressor of CPT-1, and the malonyl CoA mimetic Ro25-0187 [{5-[2-(naphthalen-2-yloxy)-ethoxy]-thiophen-2-yl}-oxo-acetic acid]. We also show that C75 can activate CPT-1 in intact hepatocytes to levels similar to those achieved with inhibition of acetyl-CoA carboxylase, the enzyme that produces malonyl CoA. Finally, we demonstrate that concentrations of C75 sufficient for activation of CPT-1 do not displace bound malonyl CoA. We conclude that CPT-1 is an activator of human CPT-1beta and other CPT-1 isoforms but that it does not activate CPT-1 through antagonism of malonyl CoA binding.


Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/pharmacology , Carnitine O-Palmitoyltransferase/metabolism , Malonyl Coenzyme A/metabolism , Mitochondria, Heart/drug effects , Animals , Enzyme Activation/drug effects , Humans , Mitochondria, Heart/enzymology , Rats , Recombinant Proteins/metabolism , Tumor Cells, Cultured , Yeasts/genetics
9.
Bioorg Med Chem Lett ; 13(19): 3237-42, 2003 Oct 06.
Article in English | MEDLINE | ID: mdl-12951100

ABSTRACT

Acetyl CoA carboxylase (ACC) catalyzes the carboxylation of acetyl CoA to form malonyl CoA. In skeletal muscle and heart, malonyl CoA functions to regulate lipid oxidation by inhibition of carnitine palmitoyltransferase-1, an enzyme which controls the entry of long chain fatty acids into mitochondria. We have found that several members of the cyclohexanedione class of herbicides are competitive inhibitors of rat heart ACC. These compounds constitute valuable reagents for drug development and the study of ACCbeta, a validated anti-obesity target.


Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Cyclohexanes/pharmacology , Enzyme Inhibitors/pharmacology , Herbicides/pharmacology , Myocardium/enzymology , Acetyl-CoA Carboxylase/metabolism , Animals , Cyclohexanes/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Herbicides/chemistry , Rats
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