Role of β-hydroxybutyric acid in the central regulation of energy balance

Laeger, Thomas; Metges, C. C.; Kuhla, Björn

doi:10.1016/j.appet.2010.04.005

Cited by 107 publications

(89 citation statements)

References 86 publications

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“…Whether altered fasting liver metabolism influences NAFLD development is also an open question. Likewise, because b-hydroxybutyrate is both a major nutrient and a signaling molecule that coordinates fasting metabolism (Laeger et al 2010), pharmacologic manipulation of ketone body transport in such states as fasting, uncontrolled type 1 diabetes mellitus, dyslipidemia, and obesity holds therapeutic promise (Veech 2004). …”

Section: Discussionmentioning

confidence: 99%

A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting

Hugo¹,

Cruz-García²,

Karanth³

et al. 2012

Genes Dev.

119

123

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To find new genes that influence liver lipid mass, we performed a genetic screen for zebrafish mutants with hepatic steatosis, a pathological accumulation of fat. The red moon (rmn) mutant develops hepatic steatosis as maternally deposited yolk is depleted. Conversely, hepatic steatosis is suppressed in rmn mutants by adequate nutrition. Adult rmn mutants show increased liver neutral lipids and induction of hepatic lipid biosynthetic genes when fasted. Positional cloning of the rmn locus reveals a loss-of-function mutation in slc16a6a (solute carrier family 16a, member 6a), a gene that we show encodes a transporter of the major ketone body b-hydroxybutyrate. Restoring wild-type zebrafish slc16a6a expression or introducing human SLC16A6 in rmn mutant livers rescues the mutant phenotype. Radiotracer analysis confirms that loss of Slc16a6a function causes diversion of livertrapped ketogenic precursors into triacylglycerol. Underscoring the importance of Slc16a6a to normal fasting physiology, previously fed rmn mutants are more sensitive to death by starvation than are wild-type larvae. Our unbiased, forward genetic approach has found a heretofore unrecognized critical step in fasting energy metabolism: hepatic ketone body transport. Since b-hydroxybutyrate is both a major fuel and a signaling molecule in fasting, the discovery of this transporter provides a new direction for modulating circulating levels of ketone bodies in metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting

Hugo¹,

Cruz-García²,

Karanth³

et al. 2012

Genes Dev.

119

123

View full text Add to dashboard Cite

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“…The central actions of ␤ HB have been reviewed by Laeger et al ( 17 ). These include its sources; its metabolism during starvation and cellular signaling; its effects on food intake; its role in ATP production, energy metabolism, and thermogenesis; its neuroprotective effects; and its infl uence on pituitary hormone release.…”

Section: Kbs Are a "High-octane" Fuel For The Bodymentioning

confidence: 99%

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

Hashim

VanItallie

2014

Journal of Lipid Research

120

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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“…Unexpectedly, cows in the medium group mobilized high amounts of subcutaneous fat but had lower LFC and plasma NEFA and BHBA concentrations than did cows in the high group. Therefore, the demonstrated negative relationship between high BHBA concentrations and low DMI may not hold for all cows (Ingvartsen and Andersen, 2000;Laeger et al, 2010).…”

Section: Effects Of Fat Concentration In the Liver On Milk Productionmentioning

confidence: 99%

Variation in fat mobilization during early lactation differently affects feed intake, body condition, and lipid and glucose metabolism in high-yielding dairy cows

Weber

Hametner

Tuchscherer

et al. 2013

Journal of Dairy Science

176

161

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Fat mobilization to meet energy requirements during early lactation is inevitable because of insufficient feed intake, but differs greatly among high-yielding dairy cows. Therefore, we studied milk production, feed intake, and body condition as well as metabolic and endocrine changes in high-yielding dairy cows to identify variable strategies in metabolic and endocrine adaptation to overcome postpartum metabolic load attributable to milk production. Cows used in this study varied in fat mobilization around calving, as classified by mean total liver fat concentrations (LFC) postpartum. German Holstein cows (n = 27) were studied from dry off until d 63 postpartum in their third lactation. All cows were fed the same total mixed rations ad libitum during the dry period and lactation. Plasma concentrations of metabolites and hormones were measured in blood samples taken at d 56, 28, 15, and 5 before expected calving and at d 1 and once weekly up to d 63 postpartum. Liver biopsies were taken on d 56 and 15 before calving, and on d 1, 14, 28, and 49 postpartum to measure LFC and glycogen concentrations. Cows were grouped accordingly to mean total LFC on d 1, 14, and 28 in high, medium, and low fat-mobilizing cows. Mean LFC (±SEM) differed among groups and were 351 ± 14, 250 ± 10, and 159 ± 9 mg/g of dry matter for high, medium, and low fat-mobilizing cows, respectively, whereas hepatic glycogen concentrations postpartum were the highest in low fat-mobilizing cows. Cows in the low group showed the highest dry matter intake and the least negative energy balance postpartum, but energy-corrected milk yield was similar among groups. The decrease in body weight postpartum was greatest in high fat-mobilizing cows, but the decrease in backfat thickness was greatest in medium fat-mobilizing cows. Plasma concentrations of nonesterified fatty acids and β-hydroxybutyrate were highest around calving in high fat-mobilizing cows. Plasma triglycerides were highest in the medium group and plasma cholesterol concentrations were lowest in the high group at calving. During early lactation, the decrease in plasma glucose concentrations was greatest in the high group, and plasma insulin concentrations postpartum were highest in the low group. The revised quantitative insulin sensitivity check index values decreased during the transition period and postpartum, and were highest in the medium group. Plasma cortisol concentrations during the transition period and postpartum period and plasma leptin concentrations were highest in the medium group. In conclusion, cows adapted differently to the metabolic load and used variable strategies for homeorhetic regulation of milk production. Differences in fat mobilization were part of these strategies and contributed to the individual adaptation of energy metabolism to milk production.

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Role of β-hydroxybutyric acid in the central regulation of energy balance

Cited by 107 publications

References 86 publications

A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting

A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting

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

Variation in fat mobilization during early lactation differently affects feed intake, body condition, and lipid and glucose metabolism in high-yielding dairy cows

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