The liver is a metabolically flexible tissue, adapting its functions to changes in nutrient availability and physiological states. This adaptability is crucial for maintaining metabolic homeostasis and likely involves communication with the central nervous system through the liver–brain axis. The liver also receives a constant influx of nutrients, hormones and microbial metabolites from the gastrointestinal tract in a multifaceted communication network, the gut–liver–brain axis. Dysregulation of this communication can lead to hepatic encephalopathy and cognitive impairments in early-stage chronic liver disease, such as metabolic dysfunction-associated steatotic liver disease, substantially affecting patient quality of life. This Review examines key signalling pathways along the liver–brain axis: humoral signalling, including metabolites, hepatokines, toxins and inflammation, and neural pathways, focusing on afferent signalling through the common hepatic branch of the vagus nerve. We discuss how each pathway might contribute to behavioural and mood changes in chronic liver disease and the development of hepatic encephalopathy. Although the humoral effects have been studied more extensively, we propose that the afferent vagus nerve is central to liver disease-associated cognitive and behavioural complications. Finally, we highlight how new techniques and tools could advance our understanding of the gut–liver–brain communication that affects behaviour. The liver is a key metabolic organ that influences metabolic homeostasis by communicating with the central nervous system. This Review discusses the role of gut–liver–brain communication in chronic liver disease, highlighting underlying mechanisms and signalling pathways.

Background: Late-onset Alzheimer’s disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

Hepatic steatosis, a consequence of obesity, is closely associated with metabolic and cardiovascular diseases, including hypertension. Even in patients that are not hypertensive, the amount of fat in the liver is positively associated with blood pressure. We hypothesized there was an underlying mechanism linking excess fat in the liver with increased blood pressure. We have previously established that liver lipid content is positively associated with hepatic production and release of the inhibitory neurotransmitter GABA, a process dependent on both the GABA shunt and electrogenic GABA transporters. Because GABA is co-transported with 1-2 net positive charges, hepatocyte depolarization, common in obesity, encourages hepatocyte GABA release. To investigate the effect of hepatocyte depolarization, we used an adeno-associated virus to induce hepatocyte specific expression of an artificial chimeric channel that opens in the presence of an exogenous ligand causing depolarization. Inducing hepatocyte depolarization increases release of GABA and decreases hepatic vagal afferent nerve activity. We established that administering the depolarizing ligand acutely (15-40 minutes after IP administration) increased systolic (30.08 ± 5.6 mmHg), diastolic (16.47 + 4.3 mmHg), and mean blood pressure (17.85 + 4.4 mmHg) measured via telemetry devices. In hepatic vagotomized mice hepatocyte depolarization had no effect on blood pressure, establishing the key role of afferent hepatic vagal signals in regulating blood pressure. Pharmacological inhibition of the GABA shunt by daily administration of ethanolamine-O-sulfate (4 days; 8 mg/mouse/day) limited liver slice GABA release and decreased systolic, diastolic, and mean (10 ± 3.07 mmHg; P < 0.05) blood pressure in diet-induced obese mice during the first hour of the dark cycle. We subsequently knocked down GABA-transaminase with bi-weekly IP deliver of an anti-sense oligonucleotide targeted to GABA-transaminase (12.5 mg/kg). We have previously established that this decreases liver GABA-transaminase mRNA expression by 97% without affecting mRNA expression in the pancreas or brain. GABA-transaminase knockdown decreased 24h mean, systolic, and diastolic blood pressure (17 + 3, 20 +2, and 14 + 4 mmHg respectively) in obese, angiotensin II induced hypertensive (continuous delivery of angiotensin II 800 ng/kg/min by Alzet® osmotic minipump) male mice. Together this data supports a role of hepatocyte GABA production and release in the hypertension that accompanies obesity. Moreover, our results provide a mechanism by which hepatic lipid content can affect blood pressure, identifying potential targets for the treatment and prevention of obesity-induced hypertension.

Mice are a valuable model for elegant studies of complex, system-dependent diseases, including pulmonary diseases. Current tools to assess lung function in mice are either terminal or lack accuracy. We set out to develop a low-cost, accurate, head-out variable-pressure plethysmography system to allow for repeated, nonterminal measurements of lung function in mice. Current head-out plethysmography systems are limited by air leaks that prevent accurate measures of volume and flow. We designed an inflatable cuff that encompasses the mouse's neck preventing air leak. We wrote corresponding software to collect and analyze the data, remove movement artifacts, and automatically calibrate each dataset. This software calculates volume, inspiratory/expiratory time, breaths per minute, mid-expiratory flow, and end-inspiratory pause. To validate the use, we established that our plethysmography system accurately measured tidal breathing, the bronchoconstrictive response to methacholine, sex-and age-associated changes in breathing, and breathing changes associated with house dust mite sensitization. Our estimates of volume, flow, and timing of breaths are in line with published estimates, we observed dose-dependent decreases in volume and flow in response to methacholine (P < 0.05), increased lung volume, and decreased breathing rate with aging (P < 0.05), and that house dust mite sensitization decreased volume and flow (P < 0.05) while exacerbating the methacholine-induced increase in inspiratory time (P < 0.05). We describe an accurate, sensitive, low-cost, head-out plethysmography system that allows for longitudinal studies of pulmonary disease in mice. NEW & NOTEWORTHY We describe a low-cost, variable-pressure head-out plethysmography system that can be used to assess lung function in mice. A balloon cuff is inflated around the mouse's neck to prevent air leak, allowing for accurate measurements of lung volume and air flow. Custom software facilitates system calibration, removes movement artifacts, and eases data analysis. The system was validated by measuring tidal breathing, responses to methacholine, and changes associated with house dust mite sensitization, sex, and aging.

Declines in lung function worsen quality of life and increase the risk of mortality. Obesity and non-alcoholic fatty liver disease are associated with worsened lung function. To investigate this association, we assessed lung function in lean and diet-induced obese conscious mice using our newly developed leak-free head-out plethysmography system. Obesity was associated with increased volume (P<0.0001), minute ventilation (volume per minute; P<0.0001), mid-expiratory flow (flow rate at 50% expiratory volume; P<0.0001), end-inspiratory pause (pause at end of inspiration; P<0.0001) and decreased expiratory time (P<0.0001). We next compared the response to methacholine (0, 25, 50, 100 mg/ml in PBS flow 0.2ml/30sec) measured using our head-out plethysmography system with forced oscillation technique (using the standard flexiVent system) measures taken in the same mice. Many of the measures gathered using head-out plethysmography were associated with measures collected using the forced oscillation technique. Minute ventilation was most significantly associated with maximal airway resistance, maximal airway elastance, tissue damping, and tissue elastance (r=-0.59 P<0.0001; r=-0.54 P<0.005; r=-0.48 P<0.005; r=-0.40 P<0.005 respectively). Volume, corrected for energy expenditure, was most significantly associated with maximal resistance of the conducting airways (r=-0.57 P<0.0001). Although fatty liver is associated with changes in lung function, we found neither hepatic vagotomy nor knocking down obesity-induced hepatic GABA production improved lung function in obese mice. Still, our head-out plethysmography system is ideal for assessing the response to interventions aimed at improving obesity-associated declines in lung function.

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.

Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.

Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (−/−) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and −/− mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin.

With a growing population, a reliable food supply is increasingly important. Heat stress reduces livestock meat and milk production. Genetic selection of high-producing animals increases endogenous heat production, while climate change increases exogenous heat exposure. Both sources of heat exacerbate the risk of heat-induced depression of production. Rodents are valuable models to understand mechanisms conserved across species. Heat exposure suppresses feed intake across homeothermic species including rodents and production animal species. We assessed the response to early-mid lactation or late-gestation heat exposure on milk production and mammary gland development/function, respectively. Using pair-fed controls we experimentally isolated the feed intake-dependent and -independent effects of heat stress on mammary function and mass. Heat exposure (35°C, relative humidity 50%) decreased daily feed intake. When heat exposure occurred during lactation, hypophagia accounted for approximately 50% of the heat stress-induced hypogalactia. Heat exposure during middle to late gestation suppressed feed intake, which was fully responsible for the lowered mammary gland weight of dams at parturition. However, the impaired mammary gland function in heat-exposed dams measured by metabolic rate and lactogenesis could not be explained by depressed feed consumption. In conclusion, mice recapitulate the depressed milk production and mammary gland development observed in dairy species while providing insight regarding the role of feed intake. This opens the potential to apply genetic, experimental, and pharmacological models unique to mice to identify the mechanism by which heat is limiting animal production.

Although hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL-C increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (OR=0.41[0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and 9 have previously been implicated in non-alcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C, and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.

In the U.S., one in thirteen individuals have been diagnosed with asthma. Obesity increases the incidence of asthma by 56%. The degree of obesity is associated with the severity of reduction in lung volume and lung volume can be restored with weight loss. Obesity also increases the risk of hospitalization by 460%. Although asthma and altered lung function is commonly assessed with spirometry in humans, plethysmography is recommended by the American Thoracic Society for assessing lung volume. The most common and effective method for assessing lung function in mice, forced ventilation, is terminal and limited to assessing lower airway function, preventing repeated measures. We aimed to develop a head‐out, variable pressure plethysmography system that would allow for repeated sensitive assessment of lung function and volume in lean and diet‐induced obese mice while mimicking the measures in human clinical practice. Preventing air leak from the chamber is vital for recording accurate measurements in a variable pressure plethysmography system. To eliminate air leak, we created an inflatable cuff that encompassed the mouse’s neck. This allowed us to repeatedly and accurately assess airway function in mice. To validate the head‐out, variable pressure plethysmography system, we used a series of models with altered muscarinic signaling. First, we assessed the response to a nebulized bronchoconstrictor, methacholine, establishing that methacholine resulted in the expected decreased breaths/minute, increased expiratory and inspiratory time, and decreased the rate of air flow at 50% of exhalation (EF50). To assess chronic muscarinic signaling, we used an adeno‐associated viral delivery to induce expression of a mutated constitutively active muscarinic 3 receptor (Q409L M3R) in airway smooth muscle, creating a model of chronic bronchoconstriction. In mice that expressed the Q490L M3R, we similarly found a decrease in breaths/minute and an increase in expiratory and inspiratory time at tidal breathing. Finally, we observed a decrease in breaths per minute at tidal breathing in muscarinic 3 receptor knock‐out mice. In our model of diet‐induced obesity we showed that obesity increased breaths per minute and decreased expiratory time at tidal breathing relative to that observed in lean mice. We have developed a reliable tool to repeatedly assess lung function in mice using the same clinically relevant measure applied in human asthmatics. Future research will apply this tool to better understand the mechanism by which obesity alters lung function and tidal breathing volume in mice.Support or Funding InformationABRC ADHS14‐082986ABRC ADHS17‐00002043T32 HL 007249

The degree of hepatic lipid accumulation in obesity directly correlates with the severity of hyperinsulinemia and systemic insulin resistance. Here, we propose a mechanism that explains this associative link, whereby, hepatic steatosis dysregulates glucose and insulin homeostasis. Obesity-induced lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic vagal afferent nerve (HVAN) firing (22.9 ± 7.6%; P < 0.05). The HVAN plays a key role in regulating whole-body glucose homeostasis. Accordingly, we propose that dysregulated hepatocyte-vagal communication underlies the metabolic dysfunction in obesity. Using an ex vivo explant liver slice model, we showed that diet induced obesity nearly triples hepatic GABA release/mg DNA in mice (P < 0.05). We hypothesize that hepatic GABA release decreases HVAN activity to stimulate insulin release and decrease peripheral insulin sensitivity. To establish that hepatocyte depolarization encourages GABA export in obesity, we virally induced expression of Kir2.1, a hyperpolarizing channel, in hepatocytes. Kir2.1 expression decreased hepatic slice GABA release to half of that observed in control obese mice, while protecting against hyperinsulinemia and insulin resistance on a high fat diet. Hepatic GABA is synthesized by GABA-Transaminase (GABA-T). To determine the role of hepatic GABA production in diet induced metabolic dysfunction, we treated obese mice with the irreversible GABA-T inhibitors, ethanolamine-O-sulphate (EOS) or vigabatrin (8mg/day; IP). Within 5 days, GABA-T inhibition ameliorated the hyperinsulinemia and insulin resistance of obesity (P < 0.05). These improvements in glucose homeostasis are dependent on an intact HVAN, as EOS did not affect serum insulin or insulin sensitivity in obese hepatic vagotomized mice. This work establishes that limiting hepatocyte GABA production or release can mute the glucoregulatory dysfunction common to obesity. Disclosure C. Geisler: None. S. Ghimire: None. B.J. Renquist: None. Funding Arizona Biomedical Research Commission (ADHS14-082986, ADHS18-201472 to B.J.R.); American Heart Association (15BGIA25090300 to B.J.R.)

Heat stress depresses growth, lactation, and mammary development and when occurring during in utero development, may have life-long effects on meat and milk production. These phenotypic responses result in billions of dollars in losses to US animal agriculture producers annually. Implementation of heat abatement strategies (shade, misters, sprinklers, and fans) has reduced the financial burden of heat stress, but many of these cooling methods are limited to intensive production systems and are water demanding. The extensive consequences of heat stress, increasing global temperatures, water use limitations, and water run-off concerns make it imperative that animal agriculture find alternative approaches to mitigate these heat-related production losses. This review examines the common responses to heat exposure across species, including depressed feed intake, growth, and milk production, while addressing the maternal and offspring responses to heat stress during gestation. The conservation of the hypophagia and hypogalactia induced by heat exposure among homeotherms proposes that the mechanism by which heat depresses production is conserved across species. Herein, I discuss how redistribution of blood flow from the viscera to the periphery may explain production losses and propose that by preventing the adaptive decrease in visceral blood flow, we may limit production losses.

The liver x receptors (LXRs) are key regulators of systemic lipid metabolism. We identified transmembrane protein 135 (TMEM135), a peroxisomal protein with an unknown function, as a novel LXR target gene. The LXRs directly induce TMEM135 transcription in humans via an LXR response element in the 5-prime untranslated region, but do not increase Tmem135 in murine cells. Functionally, knockdown of TMEM135 in vitro and in vivo results in many features typical of peroxisomal disorders such as steatosis and reduced peroxisomal β-oxidation. Mechanistically, proteomic and Western blot analyses indicated that TMEM135 mediates import of peroxisome matrix proteins necessary for β-oxidation and bile acid synthesis. These findings indicate that TMEM135 is an LXR-inducible regulator of peroxisome catabolic and anabolic processes by mediating an auxiliary matrix protein import pathway, and thus may represent a novel therapeutic target for disorders associated with peroxisome dysfunction.

Tissue biopsy metabolic activity, assessed using the oxidation-reduction indicator resazurin, may serve as a proxy to assess energy expenditure associated with maintenance in nongrowing animals or growth rate in growing animals. Herein, we evaluate the repeatability, practicality, and sensitivity of a resazurin-based assay for ranking bovine skeletal muscle biopsies based on metabolic activity. Six yearling Holstein heifers (body weight = 330 ± 11.3 kg) were fed 4 dietary treatments consisting of high or low rumen-degradable starch and fiber arranged factorially in a partially replicated Latin square design. Periods were 18 d, consisting of 3 d for diet transition, 14 d for diet adaptation, and 1 d for sample collection. Semitendinosus biopsies were collected into ice-cold Dulbecco's modified Eagle medium (Fisher Scientific, Hampton, NH) from each heifer during each period. Analysis was initiated within an hour of sample collection. To assess tissue metabolic rate, biopsies were transferred to Dulbecco's modified Eagle medium with resazurin and incubated at 37°C. Fluorescence of each sample was read at time 0 and at 15-min intervals for 2 h. Change in fluorescence was representative of skeletal muscle reducing equivalent production. Fluorescent signal strength increased with time and relative rank of treatments did not change with time; accordingly, future studies may compare fluorescence at a single time point. Change in fluorescence at 120 min was used for analysis of the fixed effects of fiber, starch, and animal when accounting for a random effect of period. Samples collected when animals were on a high-ruminally degradable starch diet were more metabolically active than samples collected from animals on low-starch diets. Significant differences in metabolic activity among individual animals were also identified. Average relative fluorescence was correlated with dry matter intake, average daily gain, and feed-to-gain ratio. The relative fluorescence tended to correlate with average daily gain (r = 0.749) and feed-to-gain ratio (r = -0.783); change in fluorescence did not correlate with dry matter intake. Although evaluated on a small sample size, this technique shows promise as a potential means of ranking animals by growth or feed efficiency. Further work on a larger experimental population is needed to confirm the usefulness of this assay as a consistent and reliable predictor of these important phenotypic parameters.

Although hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL-C increases T2D risk. We thus sought to comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that LDL-C was negatively associated with T2D (OR=0.43[0.41, 0.45] per mmol/L unit of LDL-C), despite positive associations of LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci associated with lower LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this phenotype, and 9 have previously been implicated in non-alcoholic fatty liver disease. Finally, two-sample Mendelian randomization analyses suggest that low LDL-C causes T2D, although causal interpretations are challenging due to pleiotropy. Our findings extend our current understanding of the higher T2D risk among individuals with low LDL-C, and of the underlying mechanisms, including those underlying the diabetogenic effect of LDL-C-lowering medications.

Ketosis is a metabolic adaptation to fasting, nonalcoholic fatty liver disease (NAFLD), and prolonged exercise. β-OH butyrate acts as a transcriptional regulator and at G protein-coupled receptors to modulate cellular signaling pathways in a hormone-like manner. While physiological ketosis is often adaptive, chronic hyperketonemia may contribute to the metabolic dysfunction of NAFLD. To understand how β-OH butyrate signaling affects hepatic metabolism, we compared the hepatic fasting response in control and 3-hydroxy-3-methylglutaryl-CoA synthase II (HMGCS2) knockdown mice that are unable to elevate β-OH butyrate production. To establish that rescue of ketone metabolic/endocrine signaling would restore the normal hepatic fasting response, we gave intraperitoneal injections of β-OH butyrate (5.7 mmol/kg) to HMGCS2 knockdown and control mice every 2 h for the final 9 h of a 16-h fast. In hypoketonemic, HMGCS2 knockdown mice, fasting more robustly increased mRNA expression of uncoupling protein 2 (UCP2), a protein critical for supporting fatty acid oxidation and ketogenesis. In turn, exogenous β-OH butyrate administration to HMGCS2 knockdown mice decreased fasting UCP2 mRNA expression to that observed in control mice. Also supporting feedback at the transcriptional level, β-OH butyrate lowered the fasting-induced expression of HMGCS2 mRNA in control mice. β-OH butyrate also regulates the glycemic response to fasting. The fast-induced fall in serum glucose was absent in HMGCS2 knockdown mice but was restored by β-OH butyrate administration. These data propose that endogenous β-OH butyrate signaling transcriptionally regulates hepatic fatty acid oxidation and ketogenesis, while modulating glucose tolerance.NEW & NOTEWORTHY Ketogenesis regulates whole body glucose metabolism and β-OH butyrate produced by the liver feeds back to inhibit hepatic β-oxidation and ketogenesis during fasting.

© The Author(s) 2018. Published by Oxford University Press on behalf of the American Society of Animal Science. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com. Transl. Anim. Sci. 2018.2:S185–S188 doi: 10.1093/tas/txy049