Effects of Insulin on Ketogenesis Following Fasting in Lean and Obese Men

Soeters, Maarten R.; Sauerwein, Hans P.; Faas, Linda F.; Smeenge, Martijn; Durán, Marinus; Wanders, Ronald J. A.; Ruiter, An F.C.; Ackermans, Mariëtte T.; Fliers, Eric; Houten, Sander M.; Serlie, Mireille J.

doi:10.1038/oby.2008.678

Cited by 48 publications

(42 citation statements)

References 29 publications

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“…4B). Therefore, we hypothesize that this fall in plasma insulin allowed the release and ␤-oxidation of FFA and subsequent ketone body production, as suggested previously (McGarry and Foster, 1977;Fukao et al, 2004;Soeters et al, 2009).…”

Section: Discussionmentioning

confidence: 87%

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Tremblay‐Mercier¹,

Tessier²,

Plourde³

et al. 2010

J Pharmacol Exp Ther

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Our objective was to determine whether bezafibrate, a hypotriglyceridemic drug and peroxisome proliferatoractivated receptor (PPAR)-␣ agonist, is ketogenic and increases fatty acid oxidation in humans. We measured fatty acid metabolism and ketone levels in 13 mildly hypertriglycemic adults (67 Ϯ 11 years old) during 2 metabolic study days lasting 6 h, 1 day before and 1 day after bezafibrate (400 mg of bezafibrate per day for 12 weeks). ␤-Hydroxybutyrate, triglycerides, free fatty acids, fatty acid profiles, insulin, and glucose were measured in plasma, and fatty acid ␤-oxidation was measured in breath after an oral 50-mg dose of the fatty acid tracer [U-13 C]linoleic acid. As expected, 12weeks on bezafibrate decreased plasma triglycerides by 35%. Bezafibrate tended to raise postprandial ␤-hydroxybutyrate, an effect that was significant after normalization to the fasting baseline values (p ϭ 0.03). ␤-Oxidation of [U-13 C]linoleic acid increased by 30% (p ϭ 0.03) after treatment. On the metabolic study day after bezafibrate treatment, postprandial insulin decreased by 26% (p ϭ 0.01), and glucose concentrations were lower 2 to 5 h postprandially. Thus, in hypertriglyceridemic individuals, bezafibrate is mildly ketogenic and significantly changes fatty acid metabolism, effects that may be linked to PPAR␣ stimulation and to moderately improved glucose metabolism.As the population ages, the prevalence of cognitive impairment in the elderly, particularly Alzheimer's disease (AD), is increasing markedly. Glucose is the brain's main energy substrate, providing energy to make ATP to maintain ion gradients, synaptic transmission, protein synthesis (for review, see Hoyer, 1996), and fatty acid turnover in membranes phospholipids (Rapoport et al., 2001). A decline in cerebral glucose metabolism is widely reported in AD (Foster et al., 1984;Blennow et al., 2006;Mosconi et al., 2007). This deterioration in brain fuel supply is progressive, correlates broadly with dementia severity, and may appear during normal aging at which time there can be an approximately 6% reduction in glucose uptake per decade (Petit-Taboué et al., 1998). Reduced brain glucose metabolism can arise before the clinical symptoms of AD (Reiman et al., 2004) and may contribute to neurodegenerative processes leading to AD (Liu 2004(Liu , 2008. As such, an alternative brain fuel to glucose may be therapeutically useful in AD.Physiologically, ketone bodies [or ketones; ␤-hydroxybutyrate (␤-OHB), acetoacetate, and acetone] are the main alternative energy substrate to glucose for brain metabolism and are especially important during periods of glucose deprivation. Ketones can supply up to two thirds of the energy requirement of the brain during starvation (Owen et al., 1967). Mildly increasing ketone synthesis has been proposed as a possible therapeutic approach to correct or bypass brain

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Section: Discussionmentioning

confidence: 87%

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Tremblay‐Mercier¹,

Tessier²,

Plourde³

et al. 2010

J Pharmacol Exp Ther

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“…Ketogenesis has not yet been considered as a therapeutic target. Obese humans and mice exhibit diminished whole-body ketone body turnover (26,29). Furthermore, circulating ketone body concentrations are generally decreased in obese humans (24,25,27) and serve as predictive biomarkers for conversion to type 2 diabetes in patients with impaired fasting glucose (73).…”

Section: Discussionmentioning

confidence: 99%

“…To confirm the inability of HMGCS2 ASO-treated mice to effectively incorporate fatty acid-derived carbon into ketone bodies, livers from control and HMGCS2 ASO-treated mice were perfused ex vivo via the portal vein with an oxygenated buffer containing the fatty acid [ 13 C]octanoic acid. Quantitative mapping controls (24)(25)(26)(27)(28)(29). To test the hypothesis that impaired ketogenesis, even in carbohydrate-replete and thus "nonketogenic" states, contributes to abnormal glucose metabolism and provokes steatohepatitis, we generated a mouse model of marked ketogenic insufficiency and used complementary systems physiological approaches and 13 C-labeling-based high-resolution measures of metabolic dynamics to characterize the wide-ranging effects of ketogenic impairment.…”

Section: Introductionmentioning

confidence: 99%

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

et al. 2014

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R e s e a R c h a R t i c l e5 1Ketogenic insufficiency causes hepatic inflammation, injury, and altered glucose metabolism in the setting of carbohydrate-replete overnutrition. To determine the effects of ketogenic insufficiency in the context of overnutrition, mice previously receiving ASOs for 2 weeks while on a standard low-fat chow diet were then maintained for 8 weeks on a 60% high-fat diet (HFD) commonly used to induce hyperglycemia, hepatic steatosis, and inflammation in WT mice. HMGCS2 immunoblots indicated that hepatic HMGCS2 mice (Supplemental Figure 2, A-C). HMGCS2 ASO-treated mice also exhibited normal serum free fatty acid (FFA) and TAG concentrations and a normal physiologic distribution of residual βOHB and AcAc (Supplemental Figure 2, D-F). Interestingly, HMGCS2 ASO-treated mice displayed mild, but very consistently elevated, blood glucose concentrations (160.9 ± 3.2 mg/dl vs. 145.0 ± 3.4 mg/dl in controls, n = 28-36/group, P = 0.0013), without changes in serum insulin concentrations (Supplemental Figure 2, G and H). C]pyruvate, quantified by NMR profiling of perfused liver extracts from ASO-treated mice fed a 60% HFD for 8 weeks. n = 4-5/group. *P < 0.05, **P < 0.01, ***P < 0.001 by Student's t test.

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“…Insulin resistance and diabetes are states in which systemic ketone body metabolism is perturbed (17,(65)(66)(67). Because altered substrate metabolism is one of the hallmark abnormalities of insulin-resistant and diabetic myocardium (5), regulation of myocardial ketone body metabolism may prove to be an important diagnostic biomarker of potential naturally occurring variations of ketolytic capacity.…”

Section: Discussionmentioning

confidence: 99%

Adaptation of Myocardial Substrate Metabolism to a Ketogenic Nutrient Environment

Wentz

d’Avignon

Weber

et al. 2010

Journal of Biological Chemistry

108

112

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Heart muscle is metabolically versatile, converting energy stored in fatty acids, glucose, lactate, amino acids, and ketone bodies. Here, we use mouse models in ketotic nutritional states (24 h of fasting and a very low carbohydrate ketogenic diet) to demonstrate that heart muscle engages a metabolic response that limits ketone body utilization. Pathway reconstruction from microarray data sets, gene expression analysis, protein immunoblotting, and immunohistochemical analysis of myocardial tissue from nutritionally modified mouse models reveal that ketotic states promote transcriptional suppression of the key ketolytic enzyme, succinyl-CoA:3-oxoacid CoA transferase (SCOT; encoded by Oxct1), as well as peroxisome proliferatoractivated receptor ␣-dependent induction of the key ketogenic enzyme HMGCS2. Consistent with reduction of SCOT, NMR profiling demonstrates that maintenance on a ketogenic diet causes a 25% reduction of myocardial 13 C enrichment of glutamate when 13 C-labeled ketone bodies are delivered in vivo or ex vivo, indicating reduced procession of ketones through oxidative metabolism. Accordingly, unmetabolized substrate concentrations are higher within the hearts of ketogenic diet-fed mice challenged with ketones compared with those of chow-fed controls. Furthermore, reduced ketone body oxidation correlates with failure of ketone bodies to inhibit fatty acid oxidation. These results indicate that ketotic nutrient environments engage mechanisms that curtail ketolytic capacity, controlling the utilization of ketone bodies in ketotic states.The mammalian heart must maintain constant levels of ATP to perform its mechanical and electrical functions. A variety of experimental approaches have established that cardiomyopathy is associated with changes in cardiac energy metabolism and that altered energy metabolism can cause cardiomyopathy (1-5). In the normal adult heart, mitochondrial oxidative phosphorylation provides more than 95% of the ATP generated. Substrate utilization is dynamic, and metabolic flexibility under differing physiological conditions is an important adaptive property of myocardium (6 -8). Adaptations over time are

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Effects of Insulin on Ketogenesis Following Fasting in Lean and Obese Men

Cited by 48 publications

References 29 publications

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Adaptation of Myocardial Substrate Metabolism to a Ketogenic Nutrient Environment

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