Hepatic fatty acid and glucose handling in metabolic disease: potential impact on cardiovascular disease risk

The prevalence of metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing. Although invariably associated with obesity, the importance of fat deposition in non-adipose tissue organs has yet to be fully explored. Pathological ectopic fat deposition within the liver (known as (MASLD)) has been suggested to underlie the development of T2DM and is now emerging as an independent risk factor for cardiovascular disease (CVD). The process of hepatic de novo lipogenesis (DNL), that is the synthesis of fatty acids from non-lipid precursors (e.g. glucose), has received much attention as it sits at the intersect of hepatic glucose and fatty acid handling. An upregulation of the DNL pathway has been suggested to be central in the development of metabolic diseases (including MASLD, insulin resistance, and T2DM). Here we review the evidence to determine if hepatic DNL may play a role in the development of MASLD and T2DM and therefore underlie an increased risk of CVD

Ketone monoester ingestion increases post-exercise serum erythropoietin concentrations in healthy men:Ketones and EPO

Intravenous ketone body infusion can increase erythropoietin (EPO) concentrations, but responses to ketone monoester ingestion postexercise are currently unknown. The purpose of this study was to assess the effect of ketone monoester ingestion on postexercise erythropoietin (EPO) concentrations. Nine healthy men completed two trials in a randomized, crossover design (1-wk washout). During trials, participants performed 1 h of cycling (initially alternating between 50% and 90% of maximal aerobic capacity for 2 min each interval, and then 50% and 80%, and 50% and 70% when the higher intensity was unsustainable). Participants ingested 0.8 g·kg-1 sucrose with 0.4 g·kg-1 protein immediately after exercise, and at 1, 2, and 3 h postexercise. During the control trial (CONTROL), no further nutrition was provided, whereas on the ketone monoester trial (KETONE), participants also ingested 0.29 g·kg-1 of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate immediately postexercise and at 1 and 2 h postexercise. Blood was sampled immediately postexercise, every 15 min in the first hour and hourly thereafter for 4 h. Serum EPO concentrations increased to a greater extent in KETONE than in CONTROL (time × condition interaction: P = 0.046). Peak serum EPO concentrations were higher with KETONE (means ± SD: 9.0 ± 2.3 IU·L-1) compared with CONTROL (7.5 ± 1.5 IU·L-1, P &lt; 0.01). Serum β-hydroxybutyrate concentrations were also higher, and glucose concentrations lower, with KETONE versus CONTROL (both P &lt; 0.01). In conclusion, ketone monoester ingestion increases postexercise erythropoietin concentrations, revealing a new avenue for orally ingestible ketone monoesters to potentially alter hemoglobin mass.NEW &amp; NOTEWORTHY To our knowledge, this study was the first to assess the effects of ketone monoester ingestion on erythropoietin concentrations after exercise. We demonstrated that ingestion of a ketone monoester postexercise increased serum erythropoietin concentrations and reduced serum glucose concentrations in healthy men. These data reveal the possibility for ketone monoesters to alter hemoglobin mass.</p

Beyond RPE: The Perception of Exercise Under Normal and Ketotic Conditions

AimSubjective perceptions of exercising exertion are integral to maintaining homeostasis. Traditional methods have utilized scores of ‘rating of perceived exertion’ (RPE) to quantify these subjective perceptions, and here we aimed to test whether RPE may encompass identifiable localized perceptions from the lungs (breathlessness) and legs (leg discomfort), as well as their corresponding measures of anxiety. We utilized the intervention of ketoacidosis (via consumption of an exogenous ketone ester drink) to independently perturb exercise-related metabolites and humoral signals, thus allowing us to additionally identify the possible contributing physiological signals to each of these perceptions.MethodsTwelve trained volunteers underwent two incremental bicycle ergometer tests to exhaustion, following ingestion of either an exogenous ketone ester or a taste-matched placebo drink. Cardiorespiratory measures, blood samples and perceived exertion scales were taken throughout. Firstly, two-way repeated-measures ANOVAs were employed to identify the overall effects of ketoacidosis, followed by generalized linear mixed model regression to isolate physiological predictors contributing to each perception.ResultsRating of perceived exertion was found to contain contributions from localized perceptions of breathlessness and leg discomfort, with no measurable effect of ketoacidosis on overall exertion. Leg discomfort, anxiety of breathing and anxiety of leg discomfort were increased during ketoacidosis, and correspondingly contained pH within their prediction models. Anxiety of leg discomfort also encompassed additional humoral signals of blood glucose and ketone concentrations.ConclusionThese results indicate the presence of localized components of RPE in the form of breathlessness and leg discomfort. Furthermore, subjective perceptions of anxiety appear to result from a complex interplay of humoral signals, which may be evolutionarily important when monitoring exertion under times of metabolic stress, such as during starvation

Nutritional Ketoacidosis During Incremental Exercise in Healthy Athletes

Purpose: Ketosis, achieved through ingestion of ketone esters, may influence endurance exercise capacity by altering substrate metabolism. However, the effects of ketone consumption on acid-base status and subsequent metabolic and respiratory compensations are poorly described.Methods: Twelve athletically trained individuals completed an incremental bicycle ergometer exercise test to exhaustion following the consumption of either a ketone ester [(R)-3-hydroxybutyrate-(R)-1,3-butanediol] or a taste-matched control drink (bitter flavoured water) in a blinded, cross-over study. Respiratory gases and arterialised blood gas samples were taken at rest and at regular intervals during exercise.Results: Ketone ester consumption increased blood D-β-hydroxybutyrate concentration from 0.2 to 3.7 mM/L (p &lt; 0.01), causing significant falls versus control in blood pH to 7.37 and bicarbonate to 18.5 mM/L before exercise. To compensate for ketoacidosis, minute ventilation was modestly increased (p &lt; 0.05) with non-linearity in the ventilatory response to exercise (ventilatory threshold) occurring at a 22 W lower workload (p &lt; 0.05). Blood pH and bicarbonate concentrations were the same at maximal exercise intensities. There was no difference in exercise performance having consumed the ketone ester or control drink.Conclusion: Athletes compensated for the greater acid load caused by ketone ester ingestion by elevating minute ventilation and earlier hyperventilation during incremental exercise

β-Hydroxybutyrate Oxidation in Exercise Is Impaired by Low-Carbohydrate and High-Fat Availability.

Purpose: In this study, we determined ketone oxidation rates in athletes under metabolic conditions of high and low carbohydrate (CHO) and fat availability. Methods: Six healthy male athletes completed 1 h of bicycle ergometer exercise at 75% maximal power (WMax) on three occasions. Prior to exercise, participants consumed 573 mg·kg bw-1 of a ketone ester (KE) containing a 13C label. To manipulate CHO availability, athletes undertook glycogen depleting exercise followed by isocaloric high-CHO or very-low-CHO diets. To manipulate fat availability, participants were given a continuous infusion of lipid during two visits. Using stable isotope methodology, β-hydroxybutyrate (βHB) oxidation rates were therefore investigated under the following metabolic conditions: (i) high CHO + normal fat (KE+CHO); (ii) high CHO + high fat KE+CHO+FAT); and (iii) low CHO + high fat (KE+FAT). Results: Pre-exercise intramuscular glycogen (IMGLY) was approximately halved in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both p < 0.05). Blood free fatty acids (FFA) and intramuscular long-chain acylcarnitines were significantly greater in the KE+FAT vs. other conditions and in the KE+CHO+FAT vs. KE+CHO conditions before exercise. Following ingestion of the 13C labeled KE, blood βHB levels increased to ≈4.5 mM before exercise in all conditions. βHB oxidation was modestly greater in the KE+CHO vs. KE+FAT conditions (mean diff. = 0.09 g·min-1, p = 0.03; d = 0.3), tended to be greater in the KE+CHO+FAT vs. KE+FAT conditions (mean diff. = 0.07 g·min-1; p = 0.1; d = 0.3) and were the same in the KE+CHO vs. KE+CHO+FAT conditions (p < 0.05; d < 0.1). A moderate positive correlation between pre-exercise IMGLY and βHB oxidation rates during exercise was present (p = 0.04; r = 0.5). Post-exercise intramuscular βHB abundance was markedly elevated in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both, p < 0.001; d = 2.3). Conclusion: βHB oxidation rates during exercise are modestly impaired by low CHO availability, independent of circulating βHB levels

Tribal casinos in California: the last vestige of indoor smoking

Background. High levels of airborne particles from secondhand smoke have been reported in California Indian casinos. Yet, little is known regarding the smoking status of casino patrons, their avoidance of secondhand smoke while visiting, and their views on a hypothetical smoking ban. Methods. Predictors of visiting an Indian casino were assessed among participants of the 2008 California Tobacco Survey (n = 10, 397). Exposure to and avoidance of secondhand smoke were subsequently analyzed among a subset of participants who had visited a casino in the year prior to the survey (n = 3, 361). Results. Ethnic minorities, older individuals, current smokers and residents of sparsely populated regions of California were more likely than other demographic groups to visit a tribal casino. Avoidance of secondhand smoke was more frequent among the never smokers than former and current smokers, particularly those who last visited a casino lacking physical separation between non-smoking and smoking sections. The never smokers versus current smokers disproportionately expressed a willingness to extend their stay and visit again if smoking were prohibited. Conclusions. If casinos became smoke free, then it is anticipated that they would be visited by a significantly larger number of Californians, including both patrons and those who otherwise would not have visited a casino. © 2012 Timberlake et al; licensee BioMed Central Ltd