Ketone Utilization Research Articles

Rebuttal from Manoja K. Brahma, Adam R. Wende and Kyle S. McCommis.

Drs Karwi and Lopaschuk have provided compelling evidence of the potential for ketone bodies to provide an extra source of ATP for the heart. The foundation of our opposing views most likely stems from comparing analyses of the acute effects of ketone bodies in predominantly ex vivo studies to that which occurs in vivo with more chronic ketosis. Likewise, we must all be more prudent when comparing cardiac metabolic adaptations to physiological ketosis to those observed with ‘pure’ ketosis as occurs with consumption of ketone esters or salts, or ketone infusion. In physiological states of ketosis such as fasting or consumption of a low-carbohydrate, high-fat ketogenic diet, hearts preferentially downregulate ketolytic enzymes, decreasing ketone oxidation and enhancing fatty acid oxidation (Wentz et al. 2010; McCommis et al. 2020). This downregulation of ketolytic enzymes also occurs in the hearts of diabetic mice, or in hearts overexpressing glucose transporter 4 with enhanced glucose uptake and utilization (Brahma et al. 2020). However, cardiac ketone metabolism may be directly enhanced if delivery of lipids or glucose is not concurrently elevated. Recent studies suggest that ketone ester supplementation enhanced cardiac ketone uptake in humans (Monzo et al. 2020), and ketone ester-enriched diets increased the expression of ketolytic enzymes in the rat heart (Yurista et al. 2020). These studies imply that elevated ketone extraction is associated with increased oxidation, but neither of these studies directly measured oxidation. We agree that ketone utilization appears to be more important in failing hearts. Failing hearts from humans and rodent models display enhanced expression of the ketolytic enzymes β-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA:3-oxoacid CoA transferase (SCOT) and have been shown to extract more ketones than non-failing hearts (Aubert et al. 2016; Bedi et al. 2016; Horton et al. 2019; Monzo et al. 2020; Murashige et al. 2020). Also, cardiac-specific deletion of BDH1 or SCOT in mice exacerbates cardiac dysfunction and remodelling when challenged by pressure overload (Schugar et al. 2014; Horton et al. 2019). But these knockout mouse models provide perhaps the most significant evidence that ketone body metabolism is not critical for normal hearts, as deletion of BDH1 or SCOT does not directly induce cardiac dysfunction, and these hearts can even normally adapt to physiological ketosis (Schugar et al. 2014; Horton et al. 2019). To conclude, further investigation is needed to better understand the importance of ketone body metabolism in heart failure, as well as in response to ketosis as a potential therapy for heart failure. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘Last Word’. Please email your comment, including a title and a declaration of interest, to [email protected]. Comments will be moderated and accepted comments will be published online only as ‘supporting information’ to the original debate articles once discussion has closed. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. All authors conceived, wrote, and edited this manuscript. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. A.R.W. is supported by NIH R01 HL133011. K.S.M. is supported by NIH R00 HL136658.

Beneficial effects on kidney during treatment with sodium-glucose cotransporter 2 inhibitors: proposed role of ketone utilization.

Modestly elevated circulating levels of the ketone β-hydroxybutyrate (βOHB) during treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors cause different beneficial effects on organs and cells, depending on the succinyl-CoA:3-ketoacid CoA transferase (SCOT) level. In the failing heart, SCOT is highly expressed/up-regulated, and thus, βOHB may be an energy source, in addition to fat and glucose oxidation. However, SCOT is not highly expressed/down-regulated in the kidney, and thus, βOHB may cause different beneficial effects, rather than acting as an alternative energy source in patients with chronic kidney disease (CKD). βOHB is an endogenous and specific inhibitor of class I histone deacetylases (HDACs) and the NLRP3 inflammasome, accumulates in the kidney because of its decreased utilization as an energy source due to the down-regulation of SCOT, and may induce beneficial effects such as inhibiting inflammation, oxidative stress, and fibrosis. In addition to restoring tubulo-glomerular feedback and improving renal proximal tubule oxygenation, SGLT2 inhibitors may play a renoprotective role by way of βOHB in patients with CKD.

Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases.

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

Monitoring of Energy Metabolism by Organic Acid Profiling Analysis in Plasma of Type 2 Diabetic Mice

Objective:: This study was conducted to investigate energy metabolism based on changes in organic acids in diabetes and to establish a correlation between metabolites or bone microarchitecture and the glucose index in type 2 diabetic mice. Method:: Seven-week-old male C57BL/6 mice were randomly divided into a non-diabetic group and a diabetic group. The diabetic group was fed a high-fat diet (HFD) that induced insulin resistance for 5 weeks. Afterwards, diabetes was induced by a single streptozotocin injection. Both the groups were fed a normal diet and HFD diet for 9 weeks. Results:: The fasting blood glucose level glycosylated hemoglobin (HbA1c) significantly increased in diabetic mice. Bone-alkaline phosphatase activity decreased in the diabetic group. Diabetes increased the levels of ketone bodies, including 3-hydroxybutyric, acetoacetic and butyric acid, whereas it decreased Krebs cycle components, including succinic acid and malic acid, as well as levels of glycolytic products, including lactic acid. Diabetes also induced a shortage of trabecular bone mineral density (BMD) by the regulation of trabecular morphometric parameters in the femur and tibia. Correlation analysis indicated that BMD, Krebs cycle components and lactic acid levels were negatively correlated with HbA1c, whereas ketone bodies were positively correlated with HbA1c. Conclusion: : This research suggested that uncontrolled HbA1c can affect bone loss, production of ketone bodies and utilization of glucose metabolites for energy production in type 2 diabetes.

The utility of ketones at triage: a prospective cohort study

ObjectiveTo establish the relationship between serum point-of-care (POC) ketones at triage and moderate-to-severe dehydration based on the validated Gorelick Scales.Design, setting and patientsProspective unblinded study from April 2016 to February...

Diet modulates brain network stability, a biomarker for brain aging, in young adults

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n = 292, ages 20 to 85 y; n = 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (d-β-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: A novel conceptual framework.

Long-term treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects, even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3, thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in adenosine monophosphate-activated protein kinase (AMPK) and sirtuin-1 (SIRT1) signalling, which may contribute to the development of nephropathy. These transcription factors exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signalling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms. The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain the protective effects of these drugs on the kidney in type 2 diabetes.

Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization

Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce the rate of hospitalization for heart failure in individuals with type 2 diabetes, but the underlying mechanisms remain elusive. Modestly elevated circulating β-hydroxybutyrate (βOHB) during treatment with SGLT2 inhibitors causes different beneficial effects on organs and cells, depending on succinyl-CoA:3-ketoacid CoA transferase (SCOT) levels. In the heart, in which SCOT is highly expressed/up-regulated, βOHB may be an alternative energy source apart from fat and glucose oxidation. The type 2 diabetic failing heart may be energy inefficient. In skeletal muscle, in which SCOT is not highly expressed/down-regulated, βOHB may cause antioxidant effects, resulting in amelioration of insulin resistance, which could lead to improvement in cardiac insulin resistance with metabolic, endocrine, and cytokine alterations. Although various mechanisms have been suggested, we postulate that the potential impact of SGLT2 inhibitors on heart failure lies in fuel energetics and amelioration of insulin resistance with ketone utilization depending upon SCOT levels.

Brain glucose and ketone utilization in brain aging and neurodegenerative diseases.

To meet its high energy demands, the brain mostly utilizes glucose. However, the brain has evolved to exploit additional fuels, such as ketones, especially during prolonged fasting. With aging and neurodegenerative diseases (NDDs), the brain becomes inefficient at utilizing glucose due to changes in glia and neurons that involve glucose transport, glycolytic and Krebs cycle enzyme activities, and insulin signaling. Positron emission tomography and magnetic resonance spectroscopy studies have identified glucose metabolism abnormalities in aging, Alzheimer's disease (AD) and other NDDs in vivo. Despite glucose hypometabolism, brain cells can utilize ketones efficiently, thereby providing a rationale for the development of therapeutic ketogenic interventions in AD and other NDDs. This review compares available ketogenic interventions and discusses the potential of the potent oral Ketone Ester for future therapeutic use in AD and other NDDs characterized by inefficient glucose utilization.

Remodeling of substrate consumption in the murine sTAC model of heart failure

BackgroundEnergy metabolism and substrate selection are key aspects of correct myocardial mechanical function. Myocardial preference for oxidizable substrates changes in both hypertrophy and in overt failure. Previous work has shown that glucose oxidation is upregulated in overpressure hypertrophy, but its fate in overt failure is less clear. Anaplerotic flux of pyruvate into the tricarboxylic acid cycle (TCA) has been posited as a secondary fate of glycolysis, aside from pyruvate oxidation or lactate production. Methods and resultsA model of heart failure that emulates both valvular and hypertensive heart disease, the severe transaortic constriction (sTAC) mouse, was assayed for changes in substrate preference using metabolomic and carbon-13 flux measurements. Quantitative measures of O2 consumption in the Langendorff perfused mouse heart were paired with 13C isotopomer analysis to assess TCA cycle turnover. Since the heart accommodates oxidation of all physiological energy sources, the utilization of carbohydrates, fatty acids, and ketones were measured simultaneously using a triple-tracer NMR method. The fractional contribution of glucose to acetyl-CoA production was upregulated in heart failure, while other sources were not significantly different. A model that includes both pyruvate carboxylation and anaplerosis through succinyl-CoA produced superior fits to the data compared to a model using only pyruvate carboxylation. In the sTAC heart, anaplerosis through succinyl-CoA is elevated, while pyruvate carboxylation was not. Metabolomic data showed depleted TCA cycle intermediate pool sizes versus the control, in agreement with previous results. ConclusionIn the sTAC heart failure model, the glucose contribution to acetyl-CoA production was significantly higher, with compensatory changes in fatty acid and ketone oxidation not reaching a significant level. Anaplerosis through succinyl-CoA is also upregulated, and is likely used to preserve TCA cycle intermediate pool sizes. The triple tracer method used here is new, and can be used to assess sources of acetyl-CoA production in any oxidative tissue.

Metal-Free Cyclopropanol Ring-Opening C(sp3)-C(sp2) Cross-Couplings with Aryl Sulfoxides.

A metal-free method for formal β-arylation/heteroarylation of ketones through efficient cyclopropanol ring-opening cross-couplings with aryl sulfoxides at room temperature has been developed. This protocol shows a broad substrate scope and promising scalability. In addition, the utility of the β-arylated ketones is further demonstrated through a variety of postcoupling transformations and synthetic applications.

Ketogenic Diet as an Adjunctive Therapy on the Treatment of Oral Tumor (P05-020-19)

ObjectivesThis case is here to demonstrate the effectiveness of the Ketogenic Diet (KD) as adjunctive therapy in the treatment of oral fibrosarcoma tumor. MethodsBrad, a five-year-old male mix-breed-dog was submitted on a ketogenic diet after mandibulectomy of the oral tumor. KD a high-fat/low-carbohydrate/adequate-protein diet has recently been proposed as adjuvant therapy in cancer treatment. KDs target the Warburg effect, a biochemical phenomenon in which cancer cells predominantly utilize glycolysis instead of oxidative phosphorylation to produce ATP; therefore, some cancers cannot metabolize ketone bodies, due to mitochondrial dysfunction and down-regulation of enzymes necessary for ketone utilization. Furthermore, by reducing blood glucose, insulin and insulin-like growth factor, the drivers of cancer cell proliferation, are also reduced in the bloodstream. ResultsThis cancer, whose origin is a mesenchymal cell and consists of a malignant tumor of fibroblasts has a reported survival times after surgical excision ranging from 7.0 to 12.2 months. After eighteen months of dietary therapy, the tumor-associated inflammation was completely reduced, and no more lesions were found during clinical exams. The dog in this study showed significant improvement and came back to his normal life and activities right at the beginning of the therapy. Today, he has a healthy happy and very active life. ConclusionsThere are alternatives other than conventional medicine. The therapy plans must include diet either as an adjuvant or whenever possible as the main treatment. Nutrition plays an important role in the future of Medicine. Nontoxic metabolic therapy is effective, and those interested in cancer prevention should know about this. Although the study was managed in a dog, the ketogenic diet is effective in preventing and reducing cancer risks in humans. Integrative Medicine conducted with criteria and responsibility leads to health and vitality for patients. Funding SourcesN/A. Supporting Tables, Images and/or Graphs▪

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial β-hydroxybutyrate (βOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of βOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.

Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice

Hexokinase domain containing 1, a recently discovered putative fifth hexokinase, is hypothesized to play key roles in glucose metabolism. Specifically, during pregnancy in a recent genome wide association study (GWAS), a strong correlation between HKDC1 and 2-h plasma glucose in pregnant women from different ethnic backgrounds was shown. Our earlier work also reported diminished glucose tolerance during pregnancy in our whole body HKDC1 heterozygous mice. Therefore, we hypothesized that HKDC1 plays important roles in gestational metabolism, and designed this study to assess the role of hepatic HKDC1 in whole body glucose utilization and insulin action during pregnancy. We overexpressed human HKDC1 in mouse liver by injecting a human HKDC1 adenoviral construct; whereas, for the liver-specific HKDC1 knockout model, we used AAV-Cre constructs in our HKDC1fl/fl mice. Both groups of mice were subjected to metabolic testing before and during pregnancy on gestation day 17–18. Our results indicate that hepatic HKDC1 overexpression during pregnancy leads to improved whole-body glucose tolerance and enhanced hepatic and peripheral insulin sensitivity while hepatic HKDC1 knockout results in diminished glucose tolerance. Further, we observed reduced gluconeogenesis with hepatic HKDC1 overexpression while HKDC1 knockout led to increased gluconeogenesis. These changes were associated with significantly enhanced ketone body production in HKDC1 overexpressing mice, indicating that these mice shift their metabolic needs from glucose reliance to greater fat oxidation and ketone utilization during fasting. Taken together, our results indicate that hepatic HKDC1 contributes to whole body glucose disposal, insulin sensitivity, and aspects of nutrient balance during pregnancy.

Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: A hyperpolarized 13 C magnetic resonance spectroscopy study.

AimTo investigate the effects of the sodium‐glucose co‐transporter‐2 inhibitor empagliflozin on myocardial ketone body utilization in diabetic, obese rats with spontaneously hypertensive heart failure (SHHF), after 6 months of treatment.Materials and MethodsMyocardial ketone body utilization was measured in vivo real time using a novel ketone probe (hyperpolarized [3‐13C]acetoacetate) and magnetic resonance spectroscopy (MRS). Myocardial glucose utilization and cardiac function were also determined in vivo using hyperpolarized [1‐13C]pyruvate MRS and magnetic resonance imaging (MRI), respectively. Myocardial fatty acid uptake and liver ketogenesis were assessed via protein expression.ResultsAt baseline, myocardial ketone and glucose utilization were both higher in SHHF compared with control rats. Six months of empagliflozin treatment in SHHF rats was associated with less obesity, lower blood pressure, reduced blood glucose and insulin levels, and increased fasting blood β‐hydroxybutyrate levels, as expected. Contrary to the hypothesis, myocardial ketone body utilization was lower in empagliflozin‐treated SHHF rats, while glucose utilization and cardiac function were unaltered and hepatic congestion was reduced, compared with vehicle‐treated SHHF rats.ConclusionsIn diabetic hypertensive heart disease, empagliflozin reduces afterload without altering myocardial function and glucose utilization in the face of falling blood glucose levels, but does not enhance myocardial ketone utilization despite increased circulating levels.

Sp3 C-H Arylation and Alkylation Enabled by the Synergy of Triplet Excited Ketones and Nickel Catalysts.

Triplet ketone sensitizers are of central importance within the realm of photochemical transformations. Although the radical-type character of triplet excited states of diaryl ketones suggests the viability for triggering hydrogen-atom transfer (HAT) and single-electron transfer (SET) processes, among others, their use as multifaceted catalysts in C-C bond-formation via sp3 C-H functionalization of alkane feedstocks still remains rather unexplored. Herein, we unlock a modular photochemical platform for forging C( sp3)-C( sp2) and C( sp3)-C( sp3) linkages from abundant alkane sp3 C-H bonds as functional handles using the synergy between nickel catalysts and simple, cheap and modular diaryl ketones. This method is distinguished by its wide scope that is obtained from cheap catalysts and starting precursors, thus complementing existing inner-sphere C-H functionalization protocols or recent photoredox scenarios based on iridium polypyridyl complexes. Additionally, such a platform provides a new strategy for streamlining the synthesis of complex molecules with high levels of predictable site-selectivity and preparative utility. Mechanistic experiments suggest that sp3 C-H abstraction occurs via HAT from the ketone triplet excited state. We believe this study will contribute to a more systematic utilization of triplet excited ketones as catalysts in metallaphotoredox scenarios.

AMP‐activated protein kinase in muscle is essential in ketone body utilization

BackgroundStarvation leads to a series of metabolic adaptations that enables continuous production and delivery of nutrients to critical organs, tissues and cells. Under conditions of nutrient withdrawal, ketone bodies provide an alternative source of energy for highly oxidative tissues. Although the AMP‐activated protein kinase (AMPK) is best known as a sensor of cellular energy status, its implication in ketone regulation remains unclear.ObjectiveThe aim of this study was to evaluate the effects of AMPKα2 on ketone body utilization, and to elucidate the underlying mechanisms.MethodsGlobal AMPKα2 knockout mice (AMPKα2−/−), muscle‐specific AMPKα2 knockout mice, and their age‐matched wild type (WT) littermates were subjected to either 3‐day fasting or received an intra‐peritoneal injection of β‐hydroxybutyrate salt (1.5 mg/kg body weight) to assess the β‐hydroxybutyrate consumption.ResultsFasting blood and urine ketone levels were significantly elevated in AMPKα2−/− mice when compared to their littermate WT mice. After an intra‐peritoneal bolus of β‐hydroxybutyrate, the main circulating ketone body, AMPKα2−/− mice presented a lower clearance of β‐hydroxybutyrate compared to their littermate WT mice. Further, fasting induced hyperketosis without any change in body weight or glycaemia in muscle‐specific AMPKα2 knockout mice. Consistently, these mice displayed impaired ketone utilization after β‐hydroxybutyrate injection. Furthermore, AMPKα2 deficiency in muscle significantly decreased locomotor activity, with a quicker switch from utilizing carbohydrate to fat as the predominant energy source compared to their littermate WT mice. Mechanistically, AMPKα2 deficiency in muscle presented a 50% reduced activity of succinyl‐CoA:3‐oxoacid CoA transferase compared to their littermate WT mice.ConclusionTaken together, these findings establish AMPKα2 in muscle as an essential mediator of ketolysis in fasting, through the regulation of the rate‐limiting ketolytic enzyme.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Recurrent ketoacidosis: Is it a ketone metabolism disorder?

Amac: Keton cisim olusumu (ketogenez) bozukluklari; mitokondriyel 3-hidroksi-3metil glutaril CoA sentaz (Mhs) ve 3-hidroksi-3-metil glutaril CoA liyaz (HL) enzim eksiklikleri sonucu olusur. Keton cisim yikimi (ketoliz) bozukluklari ise suksinil CoA: 3 oksoasit CoA transferaz (SCOT) ve asetoasetil CoA thiolaz-beta ketotiolaz (MAT) enzim eksiklikleri sonucu olusmaktadir. Keton metabolizma bozuklugu tanisiyla izlenen hastalarin klinik ve laboratuvar bulgulari ile degerlendirilmesi amaclandi. Yontem: Keton metabolizmasi bozuklugu tanisiyla izlenen hasta verileri retrospektif olarak incelendi. Bulgular: Dort hastada HL eksikligi, 3 hastada MAT eksikligi ve 2 hastada SCOT eksikligi tanisi mevcuttu. Hastalarin ortanca yasi 5 yil (6 ay-15,5 yil), ilk metabolik dekompanzasyon atak yasi ortalama 7,7 ay (22 gun-19 ay) idi. MAT eksikligi olan bir hasta, kardes taramasi ile asemptomatik donemde tani aldi. Iki hastada spastik tetraparezi gibi agir norolojik defisit gelisti. Dekompanzasyon ataklarinin beslenememe, kusma ve gastroenterit gibi infeksiyon sonrasi gelistigi goruldu. Sonuc: Aciklanamayan metabolik asidoz ataklari durumunda keton metabolizma bozukluklari akilda tutulmalidir. Akut dekompanzasyon degisik yaslarda ortaya cikabilir, klinik siddeti degisken olabilir. Erken tani ve uygun tedavi mortalite ve morbidite acisindan cok onemlidir.

Intermolecular Radical Addition to Carbonyls Enabled by Visible Light Photoredox Initiated Hole Catalysis.

Herein, we present a novel strategy for the utilization of simple carbonyl compounds, aldehydes and ketones, as intermolecular radical acceptors. The reaction is enabled by visible light photoredox initiated hole catalysis and the in situ Brønsted acid activation of the carbonyl compound. This regioselective alkyl radical addition reaction does not require metals, ligands or additives and proceeds with a high degree of atom economy under mild conditions. The proposed mechanism is supported by both experimental and theoretical studies.

Brain metabolism in health, aging, andneurodegeneration.

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress.