The ketone body β-hydroxybutyric acid influences agouti-related peptide expression via AMP-activated protein kinase in hypothalamic GT1-7 cells

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

doi:10.1530/joe-11-0457

Cited by 32 publications

(42 citation statements)

References 63 publications

(92 reference statements)

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“…A similar delay in the effect of ketone bodies was described previously in a hypothalamic cell line in which AMPK and mammalian target of rapamycin phosphorylation increased only after 4 h of incubation with BHB (20), thus providing a putative molecular mechanism for the BHB effect on food intake. Moreover, these authors reported that activation of these cells by BHB occurs only in high-glucose conditions (20). Thus, increased glucose oxidation induces an increase in ATP production that in turn leads first to a decrease in AMPK phosphorylation (p-AMPK).…”

Section: Discussionsupporting

confidence: 79%

“…1, H and I) after both 6 and 12 h of BHB infusion. Such an overexpression of orexigenic neuropeptides induced by ketone bodies had been described previously both in vitro in the hypothalamic GT1-7 cell line and in vivo in diabetic rats (14,20). However, it is demonstrated here that ketone bodies stimulate orexigenic neuropeptide mRNA expression also under physiological conditions in vivo.…”

Section: Discussionsupporting

confidence: 77%

“…Indeed, as described above, the stimulatory effect of BHB on food intake appears only after 4 h of treatment. The same time course was also described for the response in vitro (20). Thus, an acute exposure of brain slices to BHB might not be sufficient to observe any long-term changes in electrophysiological activity.…”

Section: Discussionmentioning

confidence: 60%

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Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

Carneiro

Geller

Fioramonti

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis. energy homeostasis; monocarboxylate transporters; ␤-hydroxybutyrate; obesity; glucose homeostasis DYSFUNCTION IN BOTH CEREBRAL DETECTION OF NUTRIENTS and integration of circulating signals has been implicated in the pathogenesis of obesity and associated disorders (11). For this reason, numerous studies have explored the possible role of nutrient and endocrine sensing of hypothalamic brain areas and their involvement in energy homeostasis regulation (34). The most studied circulating energy substrate is glucose, which represents a critical nutrient monitored by the brain. As the main energy source for brain cells, glucose also plays an important role in brain energy homeostasis (33). However, evidence showing that the brain can use alternative energy substrates has been provided. For instance, fatty acids and ketone bodies contribute significantly to fulfill brain energy needs under specific conditions (6,13,36). Despite the fact that it has been known for decades that cerebral ketone body utilization increases under particular metabolic conditions (13), central ketone body detection has been poorly studied.Under basal conditions, blood ketone body concentrations are low (Ͻ0.3 mmol/l), and their cerebral utilization is considered to be of little significance. However, ketone body levels are increased under conditions such as fasting, type 1 diabetes, or obesity (13). The brain can use ketone bodies when their blood concentrations reach Ϸ4 mmol/l, a value close to the K m of the monocarboxylate transporter 1 (MCT1) expressed on endothelial cells of cerebral blood vessels for ketone bodies (24,31,44). The brain's ability to use ketone bodies varies from...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 77%

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Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

Carneiro

Geller

Fioramonti

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…In line with this, we demonstrated that periprandial BHBA and ghrelin concentrations were inversely crosscorrelated. However, although the orexigenic property of acylated ghrelin in ruminants has recently been questioned (Iqbal et al, 2006), BHBA reduces orexigenic signaling in hypothalamic cells (Laeger et al, 2012) and food intake in small ruminants (Rossi et al, 2000). In the current study, significant cross-correlations between feed intake events and BHBA or ghrelin, respectively, could not be identified, probably because plasma samples were withdrawn at predefined hourly intervals and not in relation to single feed intake events.…”

Section: Discussionmentioning

confidence: 56%

Short-term feed intake is regulated by macronutrient oxidation in lactating Holstein cows

Derno

Nürnberg

Schön

et al. 2013

Journal of Dairy Science

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In addition to plasma metabolites and hormones participating as humoral signals in the control of feed intake, oxidative metabolic processes in peripheral organs also generate signals to terminate feeding. Although the degree of oxidation over longer periods is relatively constant, recent work suggests that the periprandial pattern of fuel oxidation is involved in regulating feeding behavior in the bovine. However, the association between periprandial oxidative metabolism and feed intake of dairy cows has not yet been studied. Therefore, the aim of this study was to elucidate possible associations existing between single feed intake events and whole-body net fat and net carbohydrate oxidation as well as their relation to plasma metabolite concentrations. To this end, 4 late-lactating cows equipped with jugular catheters were kept in respiratory chambers with continuous and simultaneous recording of gas exchange and feed intake. Animals were fed ad libitum (AL) for 24 h and then feed restricted (RE) to 50% of the previous AL intake for a further 24 h. Blood samples were collected hourly to analyze β-hydroxybutyrate (BHBA), glucose, nonesterified fatty acids (NEFA), insulin, and acylated ghrelin concentrations. Crosscorrelation analysis revealed an offset ranging between 30 and 42 min between the maximum of a feed intake event and the lowest level of postprandial net fat oxidation (FOX net ) and the maximum level of postprandial net carbohydrate oxidation (COX net ), respectively. During the AL period, FOX net did not increase above −0.2 g/min, whereas COX net did not decrease below 6 g/min before the start of the next feed intake event. A strong inverse cross-correlation was obtained between COX net and plasma glucose concentration. Direct cross-correlations were observed between COXnet and insulin, between heat production and BHBA, between insulin and glucose, and between BHBA and ghrelin. We found no cross-correlation between FOX net and NEFA. During RE, FOX net increased with an exponential slope, exceeded the threshold of −0.2 g/min as indicated by increasing plasma NEFA concentrations, and approached a maximum rate of 0.1 g/min, whereas COX net decayed in an exponential manner, approaching a minimal COX net rate of about 2.5 g/min in all cows. Our novel findings suggest that, in late-lactating cows, postprandial increases in metabolic oxidative processes seem to signal suppression of feed intake, whereas preprandially an accelerated FOX net rate and a decelerated COX net rate initiate feed intake.

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“…Moreover, BHBA is involved in ATP production, energy metabolism and thermogenesis [6]. Some studies have reported that BHBA could activate some signaling pathways as a signaling molecule and is involved in the regulation of food intake, thermogenesis, neuroprotection, and cell viability [6,7,8,9]. Even more remarkably, elevated concentrations of BHBA are related to endometritis and mastitis during the transition of dairy cows [10,11].…”

Section: Introductionmentioning

confidence: 99%

�-Hydroxybutyrate Activates the NF-κB Signaling Pathway to Promote the Expression of Pro-Inflammatory Factors in Calf Hepatocytes

Shi

Li²,

Li³

et al. 2014

Cell Physiol Biochem

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Background/Aims: ß-hydroxybutyrate (BHBA) is the major component of ketone bodies in ketosis. Dairy cows with ketosis often undergo oxidative stress. BHBA is related to the inflammation involved in other diseases of dairy cattle. However, whether BHBA can induce inflammatory injury in dairy cow hepatocytes and the potential mechanism of this induction are not clear. The NF-κB pathway plays a vital role in the inflammatory response. Methods: Therefore, this study evaluated the oxidative stress, pro-inflammatory factors and NF-κB pathway in cultured calf hepatocytes treated with different concentrations of BHBA, pyrrolidine dithiocarbamate (PDTC, an NF-κB pathway inhibitor) and N-acetylcysteine (NAC, antioxidant). Results: The results showed that BHBA could significantly increase the levels of oxidation indicators (MDA, NO and iNOS), whereas the levels of antioxidation indicators (GSH-Px, CAT and SOD) were markedly decreased in hepatocytes. The IKKß activity and phospho-IκBa (p-IκBa) contents were increased in BHBA-treated hepatocytes. This increase was accompanied by the increased expression level and transcription activity of p65. The expression levels of NF-κB-regulated inflammatory cytokines, namely TNF-a, IL-6 and IL-1ß, were markedly increased after BHBA treatment, while significantly decreased after NAC treatment. However, the p-IκBa level and the expression and activity of p65 and its target genes were markedly decreased in the PDTC + BHBA group compared with the BHBA (1.8 mM) group. Moreover, immunocytofluorescence of p65 showed a similar trend. Conclusion: The present data indicate that higher concentrations of BHBA can induce cattle hepatocyte inflammatory injury through the NF-κB signaling pathway, which may be activated by oxidative stress.

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The ketone body β-hydroxybutyric acid influences agouti-related peptide expression via AMP-activated protein kinase in hypothalamic GT1-7 cells

Cited by 32 publications

References 63 publications

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

Short-term feed intake is regulated by macronutrient oxidation in lactating Holstein cows

�-Hydroxybutyrate Activates the NF-κB Signaling Pathway to Promote the Expression of Pro-Inflammatory Factors in Calf Hepatocytes

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