Calorie restriction (CR) increases longevity and retards the development of many chronic diseases, but the underlying metabolic signals are poorly understood. Increased fatty acid (FA) oxidation and reduced FA synthesis have been hypothesized to be important metabolic adaptations to CR. However, at metabolic steady state, FA oxidation must match FA intake plus synthesis; moreover, FA intake is low, not high, during CR. Therefore, it is not clear how FA dynamics are altered during CR. Accordingly, we measured food intake patterns, whole body fuel selection, endogenous FA synthesis, and gene expression in mice on CR. Within 2 days of CR being started, a shift to a cyclic, diurnal pattern of whole body FA metabolism occurred, with an initial phase of elevated endogenous FA synthesis [respiratory exchange ratio (RER) >1.10, lasting 4-6 h after food provision], followed by a prolonged phase of FA oxidation (RER = 0.70, lasting 18-20 h). CR mice oxidized four times as much fat per day as ad libitum (AL)-fed controls (367 +/- 19 vs. 97 +/- 14 mg/day, P < 0.001) despite reduced energy intake from fat. This increase in FA oxidation was balanced by a threefold increase in adipose tissue FA synthesis compared with AL. Expression of FA synthase and acetyl-CoA carboxylase mRNA were increased in adipose and liver in a time-dependent manner. We conclude that CR induces a surprising metabolic pattern characterized by periods of elevated FA synthesis alternating with periods of FA oxidation disproportionate to dietary FA intake. This pattern may have implications for oxidative damage and disease risk.

Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates

AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation

Emerging evidence indicates that l-glutamine (Gln) plays a fundamental role in cardiovascular physiology and pathology. By serving as a substrate for the synthesis of DNA, ATP, proteins, and lipids, Gln drives critical processes in vascular cells, including proliferation, migration, apoptosis, senescence, and extracellular matrix deposition. Furthermore, Gln exerts potent antioxidant and anti-inflammatory effects in the circulation by inducing the expression of heme oxygenase-1, heat shock proteins, and glutathione. Gln also promotes cardiovascular health by serving as an l-arginine precursor to optimize nitric oxide synthesis. Importantly, Gln mitigates numerous risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, glucose intolerance, obesity, and diabetes. Many studies demonstrate that Gln supplementation protects against cardiometabolic disease, ischemia-reperfusion injury, sickle cell disease, cardiac injury by inimical stimuli, and may be beneficial in patients with heart failure. However, excessive shunting of Gln to the Krebs cycle can precipitate aberrant angiogenic responses and the development of pulmonary arterial hypertension. In these instances, therapeutic targeting of the enzymes involved in glutaminolysis such as glutaminase-1, Gln synthetase, glutamate dehydrogenase, and amino acid transaminase has shown promise in preclinical models. Future translation studies employing Gln delivery approaches and/or glutaminolysis inhibitors will determine the success of targeting Gln in cardiovascular disease.

/pdf/the-emerging-role-of-l-glutamine-in-cardiovascular-health-337eljs3a9.pdf

The Emerging Role of l-Glutamine in Cardiovascular Health and Disease.

The epidemic of the century, Diabetes Mellitus (DM) is continuously rising. Intensive research is urgently needed whereby experimental models represent an essential tool to optimise the diagnostic strategy and to improve therapy. In this review, we describe the central principles of the metabolic tests available in order to study glucose and insulin homeostasis in mice, focusing on the most widely used – the glucose and insulin tolerance tests. We provide detailed experimental procedures as well as the practical implementation of these methods and discuss the main factors that should be taken into account when using this methodology.

/pdf/guidelines-and-considerations-for-metabolic-tolerance-tests-36wfxa2cm1.pdf

Guidelines and considerations for metabolic tolerance tests in mice

The reactions of the tricarboxylic acid (TCA) cycle allow the controlled combustion of fat and carbohydrate. In principle, TCA cycle intermediates are regenerated on every turn and can facilitate t...

Ins and Outs of the TCA Cycle: The Central Role of Anaplerosis

Ammonia detoxification and gluconeogenesis are major hepatic functions mutually connected through amino acid metabolism. The liver is rich in glutamate dehydrogenase (GDH) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate and ammonia, thus bridging amino acid-to-glucose pathways. Here we generated inducible liver-specific GDH-knockout mice (HepGlud1-/- ) to explore the role of hepatic GDH on metabolic homeostasis. Investigation of nitrogen metabolism revealed altered ammonia homeostasis in HepGlud1-/- mice characterized by increased circulating ammonia associated with reduced detoxification process into urea. The abrogation of hepatic GDH also modified energy homeostasis. In the fasting state, HepGlud1-/- mice could barely produce glucose in response to alanine due to impaired liver gluconeogenesis. Compared with control mice, lipid consumption in HepGlud1-/- mice was favored over carbohydrates as a compensatory energy fuel. The changes in energy partitioning induced by the lack of liver GDH modified the circadian rhythm of food intake. Overall, this study demonstrates the central role of hepatic GDH as a major regulator for the maintenance of ammonia and whole-body energy homeostasis.

/pdf/liver-glutamate-dehydrogenase-controls-whole-body-energy-1fwrwdsjqt.pdf

Liver Glutamate Dehydrogenase Controls Whole Body Energy Partitioning Through Amino Acid-Derived Gluconeogenesis and Ammonia Homeostasis

Fructose is widely used as a sweetener in processed food and is also associated with metabolic disorders, such as obesity. However, the underlying cellular mechanisms remain unclear, in particular,...

/pdf/chronic-fructose-renders-pancreatic-b-cells-hyper-responsive-3yos96kwo5.pdf

Chronic fructose renders pancreatic β-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling

Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome gives rise to unregulated protein-induced insulin secretion from pancreatic beta-cells, fasting hypoglycemia and elevated plasma ammonia levels. Mutations associated with HI/HA were identified in the Glud1 gene, encoding for glutamate dehydrogenase (GDH). We aimed at identifying the molecular causes of dysregulation in insulin secretion and ammonia production conferred by the most frequent HI/HA mutation Ser445Leu. Following transduction with adenoviruses carrying the human GDH-wild type or GDH-S445L-mutant gene, immunoblotting showed efficient expression of the transgenes in all the investigated cell types. Enzymatic activity tested in INS-1E beta-cells revealed that the mutant was much more sensitive to the allosteric activator ADP, rendering it highly responsive to substrates. INS-1E cells expressing either the wild type or mutant GDH responded similarly to glucose stimulation regarding mitochondrial activation and insulin secretion. However, at basal glucose glutamine stimulation increased mitochondrial activity and insulin release only in the mutant cells. In mouse and human islets, expression of mutant GDH resulted in robust elevation of insulin secretion upon glutamine stimulation, not observed in control islets. Hepatocytes expressing either the wild type or mutant GDH produced similar levels of ammonia when exposed to glutamine, although alanine response was strongly elevated with the mutant form. In conclusion, the GDH-S445L mutation confers hyperactivity to this enzyme due to higher sensitivity to ADP allosteric activation. This renders beta-cells responsive to amino acid stimulation, explaining protein-induced hypoglycemia secondary to non-physiological insulin release. Hepatocytes carrying mutant GDH produced more ammonia upon alanine exposure, which underscores hyperammonemia developed by the patients.

Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia

https://archive-ouverte.unige.ch/unige:99220/ATTACHMENT01

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

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Liver Glutamate Dehydrogenase Controls Whole Body Energy Partitioning Through Amino Acid-Derived Gluconeogenesis and Ammonia Homeostasis

Chronic fructose renders pancreatic β-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling

Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?