The pharmacology and function of receptors for short-chain fatty acids

Despite some blockbuster G protein–coupled receptor (GPCR) drugs, only a small fraction (∼15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2–6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation by-products of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic β-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair

The role of B [Beta]-hydroxybutyrate in the regulation of ketogenesis in sheep

Eleven ewes weighing between 55 and 65 kg were randomly placed in one of three experimental categories: normal (n=5); diabetic insulin-treated, DIT (.n=3); and diabetic 72-hour-untreated, DUT (.n=3). Animals were rendered diabetic pharmacologically via intravenous doses of alloxan (50 mg/kg). The femoral artery and vein, along with the portal, hepatic, and mesenteric veins were cannulated immediately prior to each experiment. Experiments were therefore conducted in anesthetized (sodium pentobarbital) animals following surgery. Mesenteric infusion of para-aminohippuric acid (PAH) was used to determine whole blood flow rates across the splanchnic tissues. Three sets of preinfusion or control samples were obtained at 15-minute intervals immediately followed by continuous infusion of β-hydroxybutyrate into the caudal vena cava with four subsequent serial whole blood samples obtained from the femoral artery, and portal and hepatic veins at 30-minute intervals. The whole blood samples were analyzed for β-hydroxybutyrate, acetoacetate, and PAH, and plasma analyzed for free fatty acids and insulin. As expected, free fatty acid levels were depressed by β-hydroxy-butyrate infusion in the normal, DIT, and DUT animals. Since there was a concomitant decrease in net hepatic and total splanchnic uptake of free fatty acids, the concentration changes must have been due to decreased peripheral tissue lipolysis. Infusion of β-hydroxybutyrate increased pancreatic insulin release, but there was a corresponding hepatic uptake of the hormone, and thus, no net change in total splanchnic insulin flux was observed. In the normal and DIT, but not the DUT sheep, a net increase in total splanchnic acetoacetate uptake and a concomitant decrease in net total splanchnic β-hydroxybutyrate release during infusion of the ketone body was observed. From these results it was concluded that the effects of β-hydroxybutyrate infusion on ketone body and free fatty acid concentrations and fluxes may be mediated at the insulin receptor site and not by increased pancreatic insulin production

The Postmortem Diagnosis of Alcoholic Ketoacidosis

Aims: The aim of this article is to review the forensic literature covering the postmortem investigations that are associated with alcoholic ketoacidosis fatalities and report the results of our own analyses. Methods: Eight cases of suspected alcoholic ketoacidosis that had undergone medico-legal investigations in our facility from 2011 to 2013 were retrospectively selected. A series of laboratory parameters were measured in whole femoral blood, postmortem serum from femoral blood, urine and vitreous humor in order to obtain a more general overview on the biochemical and metabolic changes that occur during alcoholic ketoacidosis. Most of the tested parameters were chosen among those that had been described in clinical and forensic literature associated with alcoholic ketoacidosis and its complications. Results: Ketone bodies and carbohydrate-deficient transferrin levels were increased in all cases. Biochemical markers of generalized inflammation, volume depletion and undernourishment showed higher levels. Adaptive endocrine reactions involving insulin, glucagon, cortisol and triiodothyronine were also observed. Conclusions: Metabolic and biochemical disturbances characterizing alcoholic ketoacidosis can be reliably identified in the postmortem setting. The correlation of medical history, autopsy findings and biochemical results proves therefore decisive in identifying pre-existing disorders, excluding alternative causes of death and diagnosing alcoholic ketoacidosis as the cause of deat

Reprogramming of basic metabolic pathways in microbial sepsis : therapeutic targets at last?

Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems

A mathematical model of the human metabolic system and metabolic flexibility

In healthy subjects some tissues in the human body display metabolic flexibility, by this we mean the ability for the tissue to switch its fuel source between predominantly carbohydrates in the post prandial state and predominantly fats in the fasted state. Many of the pathways involved with human metabolism are controlled by insulin, and insulin- resistant states such as obesity and type-2 diabetes are characterised by a loss or impairment of metabolic flexibility. In this paper we derive a system of 12 first-order coupled differential equations that describe the transport between and storage in different tissues of the human body. We find steady state solutions to these equations and use these results to nondimensionalise the model. We then solve the model numerically to simulate a healthy balanced meal and a high fat meal and we discuss and compare these results. Our numerical results show good agreement with experimental data where we have data available to us and the results show behaviour that agrees with intuition where we currently have no data with which to compare

Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology.

Altres ajuts: C.M. is supported by the Deutsche Forschungsgemeinschaft (DFG; SFB 894, TRR-219, and Ma 2528/7-1), the German Federal Ministry of Education and Science (BMBF; 01EO1504) and the Corona foundation. J.B. is supported by the DFG (SFB 1118) and the DZHK (German Centre for Cardiovascular Research) and by the BMBF. M.L. is supported by the DFG (SFB TRR 219M-03). R.B. is supported by the Netherlands Heart Foundation (CVON DOSIS 2014-40, CVON SHE-PREDICTS-HF 2017-21, and CVON RED-CVD 2017-11); and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VIDI, grant 917.13.350). N.M. is supported by the DFG (SFB TRR 219M-03, M-05). H.T. is supported by grants from the National Institutes of Health of the US Public Health Service (HL-RO1 061483 and HL-RO1 073162). A.B.G. was supported by grants from the Ministerio de Educación y Ciencia , Fundació La MARATÓ de TV3 (201502, 201516), CIBER Cardiovascular (CB16/11/00403), and AdvanceCat 2014-2020. H.B. is supported by the DFG (Bu2126/3-1). A.D.C. was supported by 'FIL' funds for research from University of Parma. A.G. was supported by grants from the European Union Commission's FP7 programme (HOMAGE and FIBROTARGETS) and ERA-CVD Joint Transnational Call 2016 LYMIT-DIS. G.R. acknowledges recent funding from The Cunningham Trust, MRC (MR/K012924/1) and the Diabetes UK RW and JM Collins studentship. S.H. received funding from the European Union Commission's Seventh Framework programme (2007-2013) under grant agreement N° 305507 (HOMAGE), N° 602904 (FIBROTARGETS) and N° 602156 (HECATOS). S.H. acknowledges the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON-ARENA-PRIME, CVON-EARLY HFPEF, and SHE-PREDICTS. This research is co-financed as a PPP-allowance Research and Innovation by the Ministry of Economic Affairs within Top Sector Life sciences & Health

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely: 1. the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport), 2. the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently 3. the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes). This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity