Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet

Srivastava, Shireesh; Kashiwaya, Yoshiaki; King, Michael; Baxa, Ulrich; Tam, Joseph; Niu, Gang; Chen, Xiaoyuan; Clarke, Kieran; Veech, Richard L.

doi:10.1096/fj.11-200410

Cited by 108 publications

(108 citation statements)

References 60 publications

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“…During exercise, beside the role of irisin (45), any increase in lactate could contribute to the browning remodeling. This is also in agreement with a recent demonstration that a ketone ester-enriched diet activates BAT and increases Ucp1 expression in white adipose depot of C57BL/6J mice (46). It is also noteworthy that bHB constitutes a major energy metabolite for the newborn at a time where brown fat thermogenesis is crucial (47).…”

Section: Discussionsupporting

confidence: 91%

Browning of White Adipose Cells by Intermediate Metabolites: An Adaptive Mechanism to Alleviate Redox Pressure

et al. 2014

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The presence of brown adipose tissue (BAT) in human adults opens attractive perspectives to treat metabolic disorders. Indeed, BAT dissipates energy as heat via uncoupling protein (UCP)1. Brown adipocytes are located in specific deposits or can emerge among white fat through the so-called browning process. Although numerous inducers have been shown to drive this process, no study has investigated whether it could be controlled by specific metabolites. Here, we show that lactate, an important metabolic intermediate, induces browning of murine white adipose cells with expression of functional UCP1. Lactate-induced browning also occurs in human cells and in vivo. Lactate controls Ucp1 expression independently of hypoxia-inducible factor-1a and PPARa pathways but requires active PPARg signaling. We demonstrate that the lactate effect on Ucp1 is mediated by intracellular redox modifications as a result of lactate transport through monocarboxylate transporters. Further, the ketone body b-hydroxybutyrate, another metabolite that impacts redox state, is also a strong browning inducer. Because this redox-dependent increase in Ucp1 expression promotes an oxidative phenotype with mitochondria, browning appears as an adaptive mechanism to alleviate redox pressure. Our findings open new perspectives for the control of adipose tissue browning and its physiological relevance.

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Section: Discussionsupporting

confidence: 91%

Browning of White Adipose Cells by Intermediate Metabolites: An Adaptive Mechanism to Alleviate Redox Pressure

et al. 2014

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“…Additionally, such diets raise blood cholesterol and free fatty acids, increase the risk of nephrolithiasis, and cause constipation (23,116,201). Therefore, Veech and Clarke developed and tested ingestible ketone ester compounds, which can rapidly generate ketoses exceeding 5 mM in rats and humans (37,103,195), while sparing the adverse consequences of high-fat diets. A small preliminary study indicates that oral ketone esters are safe in humans (37).…”

Section: Diagnostic and Therapeutic Targets Of Ketone Body Metabolismmentioning

confidence: 99%

“…Rodents fed these compounds acutely decrease food intake. Although these animals do not exhibit changes in body weight over an extended time period, they do become more insulin sensitive, possibly because of increased expression of uncoupling proteins in brain and brown adipose tissue (103,195). Further studies will evaluate the efficacy of these compounds in the mitigation and prevention of metabolic, myocardial, and neurological diseases in rodent and human subjects.…”

Section: Diagnostic and Therapeutic Targets Of Ketone Body Metabolismmentioning

confidence: 99%

Ketone body metabolism and cardiovascular disease

Cotter

Schugar

Crawford

2013

American Journal of Physiology-Heart and Circulatory Physiology

366

304

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Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.

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“…Two KEs are known to be under current study: a ) 1,3-butanediol monoester of ␤ HB (KME) ( 77,(79)(80)(81)(82)(83)(84) and b ) 3GHB ( 48,85,86 ). Studies have demonstrated that orally or intravenously administered 1,3-butanediol or glycerol esters of ␤ HB are safe and well tolerated in animals ( 80,86 ), and that the orally administered 1,3-butanediol monoester is also safe and well tolerated in humans ( 79 ).…”

Section: Kesmentioning

confidence: 99%

“…Such degrees of hyperketonemia have been readily achieved by KE administration in rats, mice, pigs, and humans (78)(79)(80)(81)(82)(83)(84)(85)(86).…”

Section: +mentioning

confidence: 99%

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Hashim

VanItallie

2014

Journal of Lipid Research

119

108

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This article is available online at http://www.jlr.org family, its importance for purposes of this review is minimal.). KBs have been dubbed "metabolism's ugly duckling" because, in the mid-19th century, they were fi rst discovered in large quantities in the urine of patients succumbing to diabetic ketoacidosis. Thus, it is not surprising that physicians of the era considered KBs to be toxic byproducts of impaired carbohydrate metabolism. It took almost half a century for medical scientists to understand that KBs are normal metabolites manufactured by the liver in increasing amounts when dietary sources of carbohydrate and glucogenic amino acids are in short supply ( 1 ). Unfortunately, some physicians still fail to distinguish between the safe "physiological" hyperketonemia that occurs in healthy individuals during fasting or adherence to a ketogenic diet (KD), and the pathological, out-of-control hyperketonemia associated with insulin-defi cient diabetes.When Owen et al. ( 2 ) reported that during a prolonged fast KBs can provide 60% or more of the brain's daily energy requirement (thereby sparing ‫ف‬ 80 g/day of glucose that otherwise would have been derived largely from breakdown of the body's limited protein stores), it was finally acknowledged that, as in Hans Christian Andersen's 1843 fairy tale, the creature fi rst thought to be an ugly duckling was turning out to be an emerging swan. It became evident that the ketogenic response to starvation is an indispensable metabolic adaptation designed by nature to preserve strength and prolong life during times when food is unavailable ( 3 ) .It is now known that (in nondiabetic individuals), owing to the blood's effi cient buffering capacity, plasma KB Abstract Ketone bodies (KBs ), acetoacetate and ␤ -hydroxybutyrate ( ␤ HB), were considered harmful metabolic by-products when discovered in the mid-19th century in the urine of patients with diabetic ketoacidosis. It took physicians many years to realize that KBs are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KBs as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer's disease (AD), there is preliminary evidence that these same areas remain capable of metabolizing KBs. Because the ketogenic diet (KD) is diffi cult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB levels to у 2 mM, KB esters, such as 1,3-butanediol monoester of ␤ HB and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, ...

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Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet

Cited by 108 publications

References 60 publications

Browning of White Adipose Cells by Intermediate Metabolites: An Adaptive Mechanism to Alleviate Redox Pressure

Browning of White Adipose Cells by Intermediate Metabolites: An Adaptive Mechanism to Alleviate Redox Pressure

Ketone body metabolism and cardiovascular disease

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

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