Metabolic Health Research Articles

Alterations in sphingolipid synthesis during training, detraining, and retraining may alter myogenesis in skeletal muscle

The benefits of exercise on metabolic health and its effectiveness at reducing morbidity risk are well established. Exercise training enhances skeletal muscle metabolism and function, but whether such adaptations persist through detraining and how they are potentiated with retraining are not well understood. Recent evidence has highlighted the role sphingolipids play on skeletal muscle size and function, but how exercise affects sphingolipid metabolism is not yet known. We hypothesize that alterations in skeletal muscle sphingolipid metabolism with exercise training are necessary to enhance muscle mass with further exercise retraining. Here, mice were SEDentary (SED; static cages) or exercise-TRAINed (TRAIN; voluntary wheel running) and chow-fed. We performed body composition analysis (using EchoMRI) and skeletal muscle collection [tibialis anterior ( TA), extensor digitorum longus ( EDL), gastrocnemius ( Gas), Soleus ( Sol), plantaris ( Plant), and levator ani ( LA)] following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Sphingolipid and myogenic gene expression was measured in TA muscle by qPCR. Exercise training concomitantly increased lean and decreased fat percentage ( p<0.05), while increasing Sol muscle mass in TRAIN mice ( p<0.05), compared to SED. This was accompanied by higher sphingolipid metabolism ( Acer1, p<0.05; and Cers1, p=0.058) and myogenic gene expression ( MyoD, Myf5; p<0.05). Following detraining, TRAIN mice had an overall increase in lean-to-fat mass ( p<0.05) while maintaining all individual muscle masses ( p<0.05), compared to SED. This was accompanied by a reduction in gene expression of the sphingolipid receptor S1pr1 and myogenic factor Myf5 ( p<0.05), but no differences in sphingolipid metabolism ( Acer1, Cers1). Lastly, retraining increased lean and decreased fat percentage ( p<0.05) and enhanced the masses of TA, Gas, Sol, and Plant muscles in TRAIN mice ( p<0.05), compared to SED. This was accompanied by a reduced expression of rate limiting sphingolipid synthesis genes Sptlc1 and Sptlc2 and the kinase Sphk1 ( p<0.05), but no differences in Cers1 or myogenic gene expression in TRAIN mice, compared to SED. Overall, our data shows that exercise training and retraining potentiate muscle mass accretion and dynamically regulates sphingolipid metabolism adaptations. These data suggest a potential role for sphingolipids to modulate long-lasting improvements to skeletal muscle. Funding was provided by the University of Illinois Urbana-Champaign. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Gut health benefits and associated systemic effects provided by functional components from the fermentation of natural matrices.

Recently, the role of the gut microbiota in metabolic health, immunity, behavioral balance, longevity, and intestine comfort has been the object of several studies from scientific communities. They were encouraged by a growing interest from food industries and consumers toward novel fermented ingredients and formulations with powerful biological effects, such as pre, pro, and postbiotic products. Depending on the selected strains, the operating conditions, the addition of suitable reagents or enzymes, the equipment, and the reactor configurations, functional compounds with high bioactivity, such as short-chain fatty acids, gamma-aminobutyric acid, bioactive peptides, and serotonin, can be enhanced and/or produced through fermentation of several vegetable matrices. Otherwise, their formation can also be promoted directly in the gut after the dietary intake of fermented foods: In this case, fermentation will aim to increase the content of precursor substances, such as indigestible fibers, polyphenols, some amino acids, and resistant starch, which can be potentially metabolized by endogenous gut microorganisms and converted in healthy molecules. This review provides an overview of the main functional components currently investigated in literature and the associated gut health benefits. The current state of the art about fermentation technology as a promising functionalization tool to promote the direct or indirect formation of gut-health-enhancing components was deepened, highlighting the importance of optimizing microorganism selection, system setups, and process conditions according to the target compound of interest. The collected data suggested the possibility of gaining novel functional food ingredients or products rich in functional molecules through fermentation without performing additional extraction and purification stages, which are needed when conventional culture broths are used.

Lower Mitochondrial Genome Turnover and Greater Mutation Frequency in Skeletal Muscle of Aged Compared to Adult OKC-HET Rats

Mitochondrial genomic integrity, which is supported by processes such as replication, repair, and turnover, is critical in supporting metabolism and organismal health. Accumulation of mitochondrial DNA (mtDNA) mutations contributes to mitochondrial and whole-tissue dysfunction, which lead to chronic diseases including sarcopenia. The underlying mechanisms that promote generation and age-related accumulation of mtDNA mutations are unclear. mtDNA mutants may have a replicative advantage over wild-type mtDNA that propagates the accumulation of mtDNA mutations with age. However, there is limited in vivo data regarding effects of age on mtDNA replication, particularly in skeletal muscle. We hypothesized mtDNA synthesis rates would increase with age as mutation burden increased in skeletal muscle in both male and female rats. Methods: We measured mtDNA synthesis over 14 days using the stable isotope tracer deuterium oxide (D2O) and assessed mtDNA copy number and mutation deletion frequency using digital PCR in quadriceps muscle of 9- and 26 month-old (mo) male and female OKC-HET rats, which have heterogenous mtDNA backgrounds. Results: There were no differences in mtDNA copy number between sexes or ages. However, 26 month-od rats had lower rates of mtDNA synthesis compared to 9 month-old rats (9 mo: 0.509 ± 0.009 %/day, 26 month: 0.371 ± 0.048 %/day; p=0.0024) and greater mtDNA half-lives (9 mo: 132 ± 1.79 days, 216 ± 25.63 days; p=0.0009). Concomitant with lower mtDNA synthesis, 26 month-old rats had greater (p=0.003) mtDNA deletion mutation frequency (2.023e-004 ± 7.18e-005) than 9 month-old rats (9.310e-005 ± 2.404e-005). 26 month-old female rats (1.309e-004 ± 2.386e-005) had a lower (p=0.008) mutation burden than male rats (2.74e-004 ± 4.484e-005). Conclusion: Contrary to our hypothesis, mtDNA synthesis declined with age as mutation burden increased in the quadriceps. Because mtDNA copy number was not different between ages, while synthesis decreased, mtDNA turnover declined with age. Altogether, these results suggest lower mtDNA turnover rates may contribute to age-related mtDNA mutation burden. Future studies should test how modulating mtDNA turnover affects mutation frequency and mitochondrial function. This study was supported by funding from NIH grants R21AG072137 and 5T32AG052363-04. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Passive heat therapy to improve cardiometabolic health in persons with a spinal cord injury — a pilot study

Objective: To test the effect of repeated heat therapy on markers of inflammation, glucose metabolism and vascular health in persons with a spinal cord injury (SCI). It was hypothesized that the heat therapy intervention would lead to a reduction in the fasting concentration of inflammatory markers as well as an improvement in glucose tolerance and microvascular function.Methods: Five adults with thoracic SCI ((1 female, age: 43 (27 – 60) yrs, BMI: 29 (23 to 30) kg/m2, years since injury: 7 (1 – 11) yrs)) enrolled in an 8-week passive heat therapy intervention consisting of 24 session during which the oral temperature was elevated by 1°C by means of a water-perfused suit and heating blankets. The number of completed sessions, time to reach the desired oral temperature and adverse events were reported. Thermoregulatory and perceptual responses to a single passive heat therapy session were assessed during the first session of the intervention. Fasting interleukin-6 (IL-6), C-reactive protein (CRP) and glucose concentration were measured in plasma before and after the chronic intervention. Additionally, thermal hyperemia in sensate (i.e., arm) and insensate (i.e., leg) skin through laser Doppler flowmetry were determined at 39°C and 45°C pre- and post-intervention. Descriptive data are expressed as median (range).Results: The median time to reach a 1°C increase in oral temperature during passive heating was 53 (49 – 75) min, which was accompanied by a final mean skin temperature of 38.6 (36.5 – 38.9)°C, a thermal comfort of 2 (0 – 4) on a 0 to 5 ratings scale and a basic affect of +3 (+1 - +4) on a -5 to +5 rating scale. Four out of the five participants completed all prescribed passive heating sessions. However, in two participants a number of sessions (N = 10 and 2 out of 24 sessions) were stopped at 0.8°C due to thermal discomfort. There were no skin burns or signs of autonomic dysreflexia. All participants remained hemodynamically stable throughout the sessions. Resting IL-6 and CRP changed from 3.2 (2.7 – 10.5) pg/ml to 8.1 (7.6 – 11.1) pg/ml and 0.40 (0.14 – 1.16) to 1.11 (0.51 – 1.26) pg/ml, respectively. Fasting glucose concentration changed from 90.0 (85.5 – 206.0) mg/dl to 94.5 (69 – 266) mg/dl. Cutaneous vascular conductance at 39°C as a percentage of maximal vasodilation at the arm and leg changed from 23.2 (11.2 – 36.0)% to 30.4 (13.8 – 46.1)% and 34.3 (30.4 – 49.4)% to 47.4 (6.7 – 52.8)%, respectively. Conclusion: These preliminary findings suggest that it is feasible, well-tolerated and safe for persons with SCI to engage in repeated heat therapy. A full data set of this ongoing study is needed to provide more conclusive insight into its effects on cardiometabolic health outcomes. VA Rehabilitation R&D (I21RX003724-01A1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Assessing the impact of body mass index on insulin resistance and metabolic risk factors in pre-diabetic individuals: A comprehensive cross-sectional study

Background: Insulin resistance plays a crucial role in the onset of type 2 diabetes, with body mass index (BMI) being a significant determinant. Aims and Objectives: This study examines the link between BMI and insulin resistance in pre-diabetic individuals to inform strategies for early diabetes intervention. Materials and Methods: This cross-sectional study involved 100 pre-diabetic participants. Data on demographic characteristics, BMI, insulin resistance (measured by the Homeostatic Model Assessment for Insulin Resistance, HOMA-IR), lipid profiles, and blood pressure (BP) were collected. Participants were categorized into normal weight, overweight, and obese groups to explore the relationship between BMI and insulin resistance and its impact on metabolic and cardiovascular health. Results: The average participant age was 45.8 years (SD=12.3), with a slight majority being female (52%) and an average BMI of 28.4 kg/m² (SD=4.5). A significant positive correlation (r=0.64, P<0.001) between BMI and the HOMA-IR index highlighted the association between increased BMI and insulin resistance. Obese individuals had a notably higher HOMA-IR index (3.5±1.3) compared to those overweight (2.5±1.0) and of normal weight (1.9±0.8). In addition, the study found worsening lipid profiles and increased BP with higher BMI categories. Gender did not significantly affect insulin resistance, whereas a slight increase in HOMA-IR with age was noted (r=0.23, P=0.02). Conclusion: The findings highlight the strong correlation between higher BMI and increased insulin resistance in pre-diabetics. They emphasize the importance of managing body weight to mitigate the risk of diabetes and cardiovascular diseases.

Translational Science Approaches for Food Insecurity Research

Food insecurity is a pervasive problem that impacts health and well-being across the lifespan. The human research linking food insecurity to poor metabolic and behavioral health outcomes is inherently correlational and suffers from a high degree of variability both between households and even within the same household over time. Further, food insecurity is impacted by societal and political factors that are largely out of the control of individuals, which narrows the range of intervention strategies. Animal models of food insecurity are being developed to address some of the barriers to mechanistic research. However, animal models are limited in their ability to consider some of the more complex societal elements of the human condition. We believe that understanding the role that food insecurity plays in ingestive behavior and chronic disease requires a truly translational approach, and that understanding the health impacts of this complex social phenomenon requires understanding both its psychological and physiological dimensions. This brief review will outline some key features of food insecurity, highlighting those that are amenable to investigation with controlled animal models and identifying areas where integrating animal and human studies can improve our understanding of the psychological burden and health impacts of food insecurity. In the interest of brevity, this review will largely focus on food insecurity in the United States, as the factors that contribute to food insecurity vary considerably across the globe.

Sulfonamide-induced DNA hypomethylation disturbed sugar metabolism in rice (Oryza sativa L.)

DNA methylation is well-accepted as a bridge to unravel the complex interplay between genome and environmental exposures, and its alteration regulated the cellular metabolic responses towards pollutants. However, the mechanism underlying site-specific aberrant DNA methylation and metabolic disorders under pollutant stresses remained elusive. Herein, the multilevel omics interferences of sulfonamides (i.e., sulfadiazine and sulfamerazine), a group of antibiotics pervasive in farmland soils, towards rice in 14 days of 1 mg/L hydroponic exposure were systematically evaluated. Metabolome and transcriptome analyses showed that 57.1–71.4 % of mono- and disaccharides were accumulated, and the differentially expressed genes were involved in the promotion of sugar hydrolysis, as well as the detoxification of sulfonamides. Most differentially methylated regions (DMRs) were hypomethylated ones (accounting for 87–95 %), and 92 % of which were located in the CHH context (H = A, C, or T base). KEGG enrichment analysis revealed that CHH-DMRs in the promoter regions were enriched in sugar metabolism. To reveal the significant hypomethylation of CHH, multi-spectroscopic and thermodynamic approaches, combined with molecular simulation were conducted to investigate the molecular interaction between sulfonamides and DNA in different sequence contexts, and the result demonstrated that sulfonamides would insert into the minor grooves of DNA, and exhibited a stronger affinity with the CHH contexts of DNA compared to CG or CHG contexts. Computational modeling of DNA 3D structures further confirmed that the binding led to a pitch increase of 0.1 Å and a 3.8° decrease in the twist angle of DNA in the CHH context. This specific interaction and the downregulation of methyltransferase CMT2 (log2FC = –4.04) inhibited the DNA methylation. These results indicated that DNA methylation-based assessment was useful for metabolic toxicity prediction and health risk assessment.

Isotope-guided metabolomics dissects kidney arginine metabolism

Background: L-arginine is a key amino acid for detoxification, protein metabolism, and kidney and cardiovascular health. In the urea cycle, ammonia is incorporated into urea through the transformation of arginine to ornithine and urea, a reaction that occurs mostly in the liver but also in the kidneys. Hypothesis: An imbalance of kidney arginine metabolism can be associated with kidney injury. Aim: To detect the arginine uptake and its metabolic fate in kidney in vivo and ex vivo models by metabolic flux analysis. Method: Healthy C57BL/6 mice (n=22) were fed with normal and 13C6-15N4-arginine diet for 1, 2 and 8 weeks. Extracted metabolites from kidney cortex and medulla were analyzed with UHPLC/QQQ-based mass spectrometry targeting arginine-related metabolic pathways: the urea cycle, polyamines, the nitric oxide pathway, arginine/proline/glutamate interconversion, as well as modified forms of arginine. Additionally, micro-dissected nephron segments (glomeruli, proximal convoluted tubules (PCT), proximal straight tubules (PST), thin ascending limb of the loop of Henle (TAL), distal convoluted tubules (DCT), collecting ducts (CD)) from 4 healthy C57BL/6 mice, were incubated with 13C6-arginine and analyzed accordingly. Results: Isotope tracing allowed us to follow the fate of arginine in the kidney cortex and medulla of the 13C6-15N4-arginine-fed animals. The ex vivo experiments confirmed that all nephron segments take up and metabolize arginine, except for the TAL. More specifically, ornithine was found in all segments apart from the CD. Agmatine was formed in the PST and the CD, whereas arginine contributed to the proline and glutamine formation in the glomeruli, the PCT and the CD. Methylated forms of arginine were observed in the PST and the DCT. Conclusion: This study enabled the detection of arginine-related metabolites inside the kidney and showed that the metabolic fate of arginine differs along the nephron. The detailed isotope-based arginine metabolic flux and its role in kidney disease models will be determined next. This work is supported by the Young Investigator Award from the Novo Nordisk Foundation (grant number NNF19OC0056043), awarded to Markus Rinschen. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of dietary vitamin D3 and carbohydrate levels on growth performance, carbohydrate metabolism, and intestinal health of yellow catfish (Pelteobagrus fulvidraco)

The study was performed to determine effects of vitamin D3 (VD3) and carbohydrate levels in the diets on growth, carbohydrate absorption and metabolism, and intestinal health of yellow catfish (Pelteobagrus fulvidraco). Four groups of yellow catfish with an average weight of 4.12 ± 0.00 g were provided with diets containing varying proportions of VD3 and carbohydrate. These diets included two VD3 levels at 1000 IU/kg (basic VD3) and 16,100 IU/kg diet (high VD3), each containing carbohydrate levels of 25% and 35%, respectively. After analyzing dietary VD3 and carbohydrate contents, these groups were labeled as follows: the control (30.78% carbohydrates +1040 IU/kg), the VD3 group (30.67% carbohydrates +16,041 IU/kg), the high-carbohydrate group (HCD group, 39.65% carbohydrates +1017 IU/kg), and the HCD + VD3 group (39.67% carbohydrates +16,061 IU/kg). Each tank consisted of three replicates, with each replicate containing 30 fish. The experiment continued for 10 weeks. Compared with the control, HCD group reduced growth performance, the muscular layer thickness, the zonulae occludentes1 and 3 (zo1, zo3), junctional adhesion molecules 3a (jam3a), claudin1, occludin, phosphoglucomutase 1 (pgm1) mRNA expression, but increased intestinal villi height, glycogen content, glycogen synthase (gs), glycogen branching enzyme (gbe), sodium/glucose cotransporter 1 and 2 (sglt1, sglt2) and glucose transporter 2 (glut2) mRNA expression, solute carrier family 5 member 1 (SGLT1) protein expression, and dietary VD3 group alleviated HCD-induced variations of these indices mentioned above. Compared to the control, HCD group significantly suppressed pyruvate carboxylase b (pcxb), phosphoenolpyruvate carboxykinase (pepck), interleukin10 (il10), NFE2 like bZIP transcription factor 2 (nrf2), superoxide dismutase 2 (sod2) and catalase 1 (cat1) mRNA expression, and also inhibited the activities of glutathione peroxidase (GPX), catalase (CAT), total superoxide dismutase (T-SOD) and total antioxidant capacity (T-AOC), but increased hexokinase 1 (hk1), glucokinase (gk), 1-phosphofructokinase (pfkb), interleukin 1β (il1β), interleukin 6 (il6), tumor necrosis factor a and β (tnfa, tnfβ) mRNA expression, and malondialdehyde (MDA) content; dietary VD3 group further suppressed gluconeogenic genes (pcxb, pepck) expression, but significantly enhanced the expression of glycolytic genes (hk1, gk, pfkp). Dietary VD3 also alleviated HCD-induced variations of these indices involved in antioxidant and inflammatory responses in yellow catfish intestine. Based on these results, our study indicated that dietary VD3 contributed to alleviate HCD-induced adverse effects on intestinal carbohydrate utilization and health. Our study also elucidated the innovative insights into the interaction of HCD and VD3 in fish, and provided the potential strategies for improving dietary carbohydrate utilization of fish via VD3 addition in aquafeeds. These findings can potentially contribute to cost savings for businesses and serve as a reference for optimizing feed formulations.

Tomato genotype but not crop water deficit matters for tomato health benefits in diet-induced obesity of C57BL/6JRj male mice

Several studies have linked the intake of lycopene and/or tomato products with improved metabolic health under obesogenic regime. The aim was to evaluate the differential impact of supplementations with several tomato genotypes differing in carotenoid content and subjected to different irrigation levels on obesity-associated disorders in mice. In this study, 80 male C57BL/6JRj mice were assigned into 8 groups to receive: control diet, high fat diet, high fat diet supplemented at 5 % w/w with 4 tomato powders originating from different tomato genotypes cultivated under control irrigation: H1311, M82, IL6-2, IL12-4. Among the 4 genotypes, 2 were also cultivated under deficit irrigation, reducing the irrigation water supply by 50 % from anthesis to fruit harvest. In controlled irrigation treatment, all genotypes significantly improved fasting glycemia and three of them significantly lowered liver lipids content after 12 weeks of supplementation. In addition, IL6-2 genotype, rich in β-carotene, significantly limited animal adiposity, body weight gain and improved glucose homeostasis as highlighted in glucose and insulin tolerance tests. No consistent beneficial or detrimental impact of deficit irrigation to tomato promoting health benefits was found. These findings imply that the choice of tomato genotype can significantly alter the composition of fruit carotenoids and phytochemicals, thereby influencing the anti-obesogenic effects of the fruit. In contrast, deficit irrigation appears to have an overall insignificant impact on enhancing the health benefits of tomato powder in this context, particularly when compared to the genotype-related variations in carotenoid content.

Updated Reference Intervals for Alanine Aminotransferase in a Metabolically and Histologically Normal Population

Background and AimsThis study aims to reevaluate upper reference limit (URL) for alanine aminotransferase (ALT) by considering the changing epidemiology of major liver diseases. We employed histological and metabolic parameters in Asian living liver donors. MethodsWe performed a retrospective analysis of 5,455 potential living liver donors from 2005 to 2019. Participants were screened for hepatitis B, C, HIV, and alcohol use. Histologically and metabolically healthy participants were assessed using the Prati criteria (body mass index <23 kg/m2, triglyceride ≤200 mg/dL, fasting glucose ≤105 mg/dL, total cholesterol ≤220 mg/dL). The updated ALT-URL was determined as the 95th percentile among participants without hepatic steatosis and who met the Prati criteria. ResultsThe median age was 30 years, with a male predominance (66.2%). Among 5,455 participants, 3,162 (58.0%) showed no hepatic steatosis, with 1,553 (49.1%) meeting both the criteria for no steatosis and the Prati criteria for metabolic health. The updated URL for ALT in these participants was 34 U/L for males and 22 U/L for females, which was significantly lower than conventionally accepted values. Using this revised ALT-URL, 72.8% of males with ALT levels ≥34 U/L and 55.0% of females with ALT levels ≥22 U/L showed signs of steatosis, while 32.7% of males and 22.2% of females met the criteria for metabolic syndrome. ConclusionsOur study provided the newly established reference intervals for ALT levels in a metabolically and histologically verified Asian population. The proposed URL for ALT are 34 U/L and 22 U/L for males and females, respectively.

Time-restricted Eating to Improve Metabolic Health: Investigating the Mechanisms Underlying Glycolytic and Lipolytic actions

Time-restricted eating (TRE) is a behavioral intervention approach motivated by the emerging role of circadian rhythms in physiology and metabolism. In this approach, all caloric intake is restricted within a regular interval of less than 12 hours, with no overt attempt to reduce calories. We present a whole-body computational model of TRE that incorporates enzyme and substrate reactions as well as hormonal actions during fasting and postprandial states. The model is divided into seven compartments: brain, heart, skeletal muscle, gastrointestinal tract, liver, adipose tissue, and other tissues. We conducted simulations to test the hypothesis that TRE modulates whole-body glucose balance by improving postprandial hyperglycemia and hypertriglyceridemia, keeping these excursions to a minimum. We simulated different TRE schedules with meals varying in fat and carbohydrate content. Our results highlight the importance of chrono-pharmacological considerations in glycemic control: TRE modulates the interplay between glycogenolysis in the liver, lipolysis in adipose tissue and fatty acid oxidation in other organs to improve glucose control. The alternation of eating and fasting, in particular, could be manipulated to balance blood sugar levels. TRE simulations have also shown beneficial effects on the lipid front, such as lower triglyceride levels and improved lipolytic effciency, meaning the body is better able to use fat stores for fuel. This work was supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The effect of fish oil rich in cetoleic acid on the omega-3 index and skin quality

Objective: The objective of the study was to provide preliminary data on the effect of a long chain monounsaturated oil rich in cetoleic acid on the omega-3 index, a validated measure of EPA and DHA in blood cells, as well as a potential effect of the oil on skin quality.Design: Two intervention studies were performed, each as double blinded, placebo controlled, randomised nutritional trials. The CetoIndex study (N=55) measured omega-3 index using a blood spot collection kit (Omegaquant). The Optihud study (N=28) measured skin quality parameters in healthy women using the VISIA system. The CRO was an oil derived from North Atlantic fish with a predominance of long chain mono-unsaturated fatty acids including cetoleic acid (C22:1 n-11) and gondoic acid (C20:1 n-9).Results: In a placebo-controlled study, the omega-3 index in healthy volunteers was increased similar to that seen with an oil with higher levels of omega-3 fatty acids. In a separate placebo-controlled study, the CRO reduced erythema in skin, which is a marker of inflammation.Conclusions: The results of this pilot study suggest that the use of a CRO increases the omega-3 index more than expected from the levels of EPA and DHA in the oil. The CRO reduced may potentially have benefits on skin inflammation.Summary: Long chain polyunsaturated fatty acids (LCPUFA), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are commonly taken as dietary supplements for a range of health benefits. Other marine fatty acids may also provide health benefits and it is of interest to understand their activity. Long chain mono-unsaturated fatty acids (LCMUFA) have shown biological activity in studies of metabolic health in animal models. Here, we report two intervention studies using a fish oil with a high LCMUFA content where cetoleic acid is the predominant fatty acid (Cetoleic rich oil: CRO). In CetoIndex, a placebo-controlled study in 55 healthy volunteers, the omega-3 index increased similarly to that seen with an oil containing higher levels of omega-3 fatty acids. In Optihud, a placebo-controlled study in 28 female volunteers, the CRO reduced erythema in skin, which is a marker of inflammation. The results of this pilot study support the use of a CRO for increasing the omega-3 index with potential benefits on skin inflammation.

No Effect of High Eating Frequency Compared with Low Eating Frequency on Appetite and Inflammation Biomarkers: Results from a Randomized Crossover Clinical Trial

BackgroundEating frequency (EF) focuses on the total number of eating occasions per day and may influence metabolic health. ObjectivesWe sought to examine the effect of high compared with low EF on appetite regulation and inflammatory biomarkers among healthy adults. MethodsData are from a randomized, crossover trial (the Frequency of Eating and Satiety Hormones study). Participants (n = 50) completed 2 isocaloric 21-d study periods of low EF (3 eating occasions/d) and high EF (6 eating occasions/d) in random order with a 14-d washout period in between. Participants were free-living and consumed their own food, using study-directed, structured meal plans with identical foods and total energy in both study periods. On days 1 and 21 of each EF period, fasting blood was collected during in-person clinic visits to assess plasma concentrations of ghrelin, leptin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP). Linear mixed models with EF, diet sequence, and period as fixed effects and participant as random effect were used to estimate the intervention effect. Interaction effects between EF and body fat percentage were examined. ResultsAmong the 50 participants who completed the trial, 39 (78%) were women, 30 (60%) were Non-Hispanic White, and 40 (80%) had a body mass index of <25 kg/m2, and the mean age was 32.1 y. The differences between high and low EF in fasting ghrelin (geometric mean difference: 17.76 ng/mL; P = 0.60), leptin (geometric mean difference: 2.09 ng/mL; P = 0.14), adiponectin (geometric mean difference: 381.7 ng/mL; P = 0.32), and hs-CRP (geometric mean difference: −0.018 mg/dL; P = 0.08) were not statistically significant. No significant interaction was observed between EF and body fat percentage on appetite regulation and inflammatory biomarkers. ConclusionsNo differences was observed in fasting ghrelin, leptin, adiponectin, and hs-CRP comparing high and low EF. Future studies are needed to understand the physiology of EF and appetite as they relate to metabolic health.This trial was registered at clinicaltrials.gov as NCT02392897.

The Expanding Problem of Regional Adiposity: Revisiting a 1985 Diabetes Classic by Ohlson etal.

Body fat distribution is a predictor of metabolic health in obesity. In this Classics in Diabetes article, we revisit a 1985 Diabetes article by Swedish investigators Ohlson etal. This work was one of the first prospective population-based studies that established a relationship between abdominal adiposity and the risk for developing diabetes. Here, we discuss evolving concepts regarding the link between regional adiposity and diabetes and other chronic disorders. Moreover, we highlight fundamental questions that remain unresolved.

Brown adipose tissue metabolism in women is dependent on ovarian status.

In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min-1) and postmenopausal women (0.63 ± 0.28 min-1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min-1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g-1·min-1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min-1 to 0.91 ± 0.41 min-1) to that observed in postmenopausal women (0.91 ± 0.63 min-1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.NEW & NOTEWORTHY In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.

Systemic inflammation in early lactation and its relation to the cows' oxidative and metabolic status, productive and reproductive performance as well as activity

A dysregulated inflammatory response contributes to the occurrence of disorders in cows during the transition period from pregnancy to lactation. However, a detailed characterization of clinically healthy cows that exhibit enhanced inflammatory response during this critical period remains incomplete. In this experiment, a total of 99 individual transition dairy cows and 109 observations (18 cows monitored in 2 consecutive lactations), submitted to similar transition management were involved to evaluate the relationship between elevated inflammatory response and metabolic, oxidative status as well as transition outcomes. Blood was taken at -7, 3, 6, 9 and 21 d in milk (DIM) and concentrations of metabolic parameters (glucose, β-hydroxybutyric acid (BHBA), nonesterified fatty acids (NEFA), insulin, insulin-like growth factor 1 (IGF-1) and fructosamine) were analyzed. Additionally, oxidative parameters (proportion of oxidized glutathione to total glutathione in red blood cells (GSSG (%)), the activity of glutathione peroxidase (GPx) and of superoxide dismutase (SOD), concentrations of malondialdehyde (MDA) and oxygen radical absorbance capacity (ORAC)) and acute phase proteins (APP) including haptoglobin (Hp), serum amyloid A (SAA) and albumin-to-globulin ratio (A:G) were determined in the blood of 21 DIM. The 3 APP parameters were used to group clinically healthy cows into 2 categories through k-medoids clustering, i.e., a group showing an acute phase response (APR, n = 39) and a group not showing such a response, i.e., non-APR (n = 50). Diseased cases (n = 20) were handled in a separate group. Lower SAA and Hp concentrations as well as higher A:G were observed in the non-APR group, although for Hp differences were observed from the APR group, not from the diseased group. Only one of the 5 oxidative parameters differed between the groups, with the non-APR group exhibiting lower GPx activity compared with the diseased group. The non-APR group showed the highest IGF-1 levels among the 3 groups, and lower NEFA concentrations compared with the diseased groups. The diseased group also showed reduced dry matter intake and milk yield compared with clinically healthy cows, regardless of their inflammatory status. Moreover, the APR group exhibited temporarily lower activity levels compared with the non-APR group. These findings highlight that cows with a lower inflammatory status after 21 DIM exhibited better metabolic health characteristics, productive performance as well as activity levels. Nevertheless, the detrimental effects of a higher inflammatory status in the absence of clinical symptoms are still relatively limited.

Estrogenic re-mapping of the metabolic response to an energy deficit

Endothermy is an adaptation that can be traced back hundreds of millions of years and is critical for nearly every aspect of mammalian biology. Despite the advantages associated with a stable internal temperature, endothermy is energetically expensive. To conserve energy when food is scarce, mice have evolved the ability to reversibly enter a regulated state of hypothermia and hypometabolism, known as torpor. We have found that circulating 17β-estradiol, a potent estrogen, inhibits fasting-induced torpor in ovariectomized female mice, yet the signaling mechanisms underlying this estrogenic re-mapping of the metabolic response to an energy deficit remain largely unknown. Recent studies have identified the medial preoptic area of the hypothalamus (MPO) as the central regulator of torpor. MPO neurons that express estrogen receptor alpha have been identified as central coordinators of torpor, and MPO neurons that are activated during torpor broadly express estrogen receptors, suggesting that circulating estrogens may directly modulate torpor-driving neurons in the MPO. To test the hypothesis that circulating estrogens inhibit torpor by acting directly on estrogen-sensitive neurons in the MPO, we delivered 17β-estradiol (E2) directly to the MPO before inducing torpor with a 48-hour fast. Surprisingly, we found that E2 delivered to the MPO was suffcient to inhibit fasting-induced torpor in gonad-intact, but not ovariectomized, female mice. These data demonstrate that E2 signaling in the MPO is insuffcient to inhibit torpor on its own and that there are likely MPO-independent nodes in the body that circulating estrogens act on to inhibit torpor. However, our data also demonstrate that E2 signaling in the MPO does play a role in tuning the torpor response when endogenous gonadal hormones are present, suggesting that the MPO can sense estrogens and engage the appropriate effector circuits to inhibit torpor in certain physiological contexts. Together, these data advance our understanding of how circulating estrogens inhibit torpor in mice — a critical step towards the broader goal of understanding how circulating estrogens influence energy expenditure, and how these pathways can be manipulated to improve metabolic health. NIH RO1 (R01AG066821) - "Estrogenic modulation of neural circuits that control temperature" AHA Predoctoral Fellowship (23PRE1019923) - Estrogenic modulation of hypothalamic neurons that control energy expenditure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A novel fatty acid mimetic with Pan-PPAR partial agonist activity inhibits diet-induced obesity and metabolic dysfunction-associated steatotic liver disease

ObjectiveThe prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice. MethodsC57Bl/6 mice (8-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis. ResultsWe found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice. ConclusionsCollectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis.

Maternal Exercise Improves Infant Mesenchymal Stem Cell Lipid Storage and Oxidation, and Decreases Infant Adiposity

Rates of pediatric obesity are continuously rising and are likely to translate into high incidence of metabolic disease later in life. Maternal exercise during pregnancy has been established as a useful non-pharmacological intervention to improve infant metabolic health; however, mechanistic insight behind these adaptations remains mostly confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to a multitude of infant peripheral tissue (e.g., skeletal muscle) and remain involved in mature tissue repair and maintenance. Importantly, these cells preserve the phenotype of an offspring donor and represent a model for the investigation of mechanisms behind infant metabolic health improvements. We used undifferentiated MSC collected during a randomized controlled trial to investigate if maternal exercise, regardless of exercise mode, affects infant adiposity and fatty acid oxidation. Compared to control, we observed &gt;160% higher neutral lipid content in Ex-MSCs (p&lt;0.01). However, this finding was coupled with significantly higher complete fatty acid oxidation to CO2 and lower incomplete fat oxidation (ASM production) in Ex-MSCs (p≤0.05). Infants in the exercise group had significantly lower body fat percentage compared to same age infants of controls at one month of age (p≤0.05). There was no difference in lean body mass volume (p&gt;0.05) or infant one-month BMI (p=0.069). Together, these data indicate that maternal exercise exposure in utero is still associated with decreased infant adiposity one month after birth. MSC lipid content was positively associated with maternal fitness and exercise volume (p&lt;0.01) during pregnancy. Finally, an increase in average maternal exercise volume (MET*min/wk; r=-0.4, p≤0.05) and total gestational MET*min (r=-0.36, p≤0.05), but not VO2max (p=0.07) was associated with infant 1-month body fat percentage. Together, these data showcase the influence of maternal exercise exposure on improvements in cellular metabolism and at 1 month of age. Collectively, our data suggests that exposure to maternal exercise could contribute to lower adiposity in early infancy. This project was supported by the American Heart Association (18IPA34150006 to L.E.M.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.