The association between serum free fatty acid levels and neurological outcomes in out-of-hospital cardiac arrest patients: A prospective observational study.

Free fatty acids (FFA) are a known risk factor in the development of sudden cardiac death. However, the relationship between FFA and the outcome of out-of-hospital cardiac arrest (OHCA) patients remains unclear. We aimed to examine the association between FFA and neurological outcomes in OHCA patients. This prospective observational study included adult (≥18 years) OHCA patients between February 2016 and December 2022. We measured serial FFA levels within 1 hour after ROSC and at 6, 12, 24, 48, and 72 hours after the return of spontaneous circulation (ROSC). The primary outcome was neurological outcome at 6 months. A poor neurological outcome was defined by cerebral performance categories 3, 4, and 5. A total of 147 patients were included. Of them, 104 (70.7%) had poor neurological outcomes, whereby the median FFA levels within 1 hour after ROSC (0.72 vs 1.01 mol/L), at 6 hours (1.19 vs 1.90 mol/L), 12 hours (1.20 vs 1.66 mol/L), and 24 hours (1.20 vs 1.95 mol/L) after ROSC were significantly lower than in good outcome group. The FFA levels at 6 hours (odds ratio, 0.583; 95% confidence interval, 0.370-0.919; P = .020), and 12 hours (odds ratio, 0.509; 95% confidence interval, 0.303-0.854; P = .011) after ROSC were independently associated with poor neurological outcomes. The lower FFA levels at 6 hours and 12 hours after ROSC were associated with poor neurological outcomes in patients with OHCA. FFA may reflect oxidative metabolism as well as oxidative stress.

Mediating effect of adiponectin between free fatty acid and tumor necrosis factor-α in patients with diabetes.

BACKGROUND/OBJECTIVES: Increased free fatty acid (FFA) promotes adiponectin secretion in healthy subjects and induces inflammation in diabetes. Given the potential pro-inflammatory role of adiponectin in "adiponectin paradox", we performed this study in patients with type 2 diabetes mellitus (T2DM) to assess the association of FFA with adiponectin and to investigate whether adiponectin mediates FFA-related inflammation. METHODS: This cross-sectional study consisted of adult patients with T2DM. FFA, adiponectin, and tumor necrosis factor-α (TNF-α) were assayed from fasting venous blood after overnight fasting for at least 8 h. Multivariable linear regression analysis and restricted cubic splines (RCS) analysis were performed to identify the association between FFA and adiponectin. Mediation analysis was performed to determine the mediating effect of adiponectin on the association between FFA and TNF-α. RESULTS: This study included 495 participants, with 332 males (67.1%) and a mean age of 47.0 ± 11.2 years. FFA was positively associated with adiponectin (b = 0.126, 95%CI: 0.036-0.215, P = 0.006) and was the main contributor to the increase of adiponectin (standardized b = 0.141). The RCS analysis demonstrated that adiponectin increased with FFA when FFA was less than 0.7 mmol/L but did not further increase thereafter (Poverall < 0.001 and Pnon-linear < 0.001). In addition, adiponectin mediated the association between FFA and TNF-α. The mediating effect was 0.08 (95%CI: 0.03-0.13, P = 0.003) and the mediating effect percentage was 26.8% (95%CI: 4.5-49.2, P = 0.02). CONCLUSIONS: In patients with T2DM, FFA was positively associated with adiponectin when FFA was less than 0.7 mmol/L. Elevated adiponectin mediated FFA-related inflammation. This study may provide insights into the pro-inflammatory effect of adiponectin in T2DM.

Relationship of postprandial fibroblast growth factor 21 with lipids, inflammation and metabolic dysfunction-associated fatty liver disease during oral fat tolerance test.

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) is closely associated with serum fibroblast growth factor (FGF) 21; however, previous studies have typically focused on the static fasting state, and the relationships between postprandial FGF21 levels, postprandial metabolic status, and MAFLD remain unclear. Therefore, we measured postprandial lipids, inflammatory factors, and FGF21 levels in MAFLD and further analyzed their relationship using an oral fat tolerance test (OFTT). Patients and methods: In total, 103 non-diabetic adult volunteers, including 46 patients with MAFLD, were included in this study. All participants underwent the OFTT. Venous blood samples were collected at 0, 2, 4, and 6 h. Circulating total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), hypersensitive-C reactive protein(hs-CRP) and FGF21 were assessed. Results: Serum FGF21 significantly increased in the fasting state (P < 0.05) and showed a biphasic change of first decreasing and then increasing in MAFLD during the OFTT. The postprandial levels of TG, TC, LDL-C, FFA, IL-6, TNF-α and hs-CRP were significantly increased in MAFLD (P < 0.05). After adjusting for multiple factors, the FGF21 incremental area under the curve (iAUC) was linearly correlated with the FFA iAUC, TG iAUC, and IL-6 iAUC (P < 0.05) and was an independent factor for MAFLD (P < 0.05, OR=1.403). Conclusion: Dyslipidemia and excessive inflammation in MAFLD are associated to FGF21 levels in the postprandial period. An abnormal postprandial FGF21 response may be an important mechanism of MAFLD.

Association between metabolic parameters and embryo production in superovulated dairy cattle.

This study aims to investigate the relationship between metabolic parameters and the number of embryos produced in superovulated cows with high genetic characteristics in milk yield. Eighteen Holstein donors were treated with classic superovulation protocols, AI and flushing. During superovulation, decreasing doses of FSH (follicle-stimulating hormone) were administered at 12-h intervals for 4 days. Plasma insulin-like growth factor (IGF1), glucose (GLU), beta-hydroxybutyric acid (BHB), non-esterified fatty acid (NEFA), blood urea nitrogen (BUN) and total protein (TP) levels were determined by using an autoanalyzer. The mixed model analysis of variance was used for statistical analysis. As a result, plasma IGF1, BHB and BUN had significant interactions with both groups and days (p < .05). Additionally, plasma TP-days interactions were significant (p < .05). Furthermore, there was a negative correlation between the number of embryos and plasma BHB levels (p < .05). In conclusion, under appropriate environmental conditions, metabolic profile control of donors can contribute to the embryo production process and to the studies on the metabolic infrastructure.

Metabolic Responses to High-Fat Feeding and Chronic Psychological Stress Combination.

INTRODUCTION: High-fat diet (HFD) consumption and being exposed to daily psychological stress, common environmental factors in modern lifestyle, play an important role on metabolic disorders such as glucose homeostasis impairment. The aim of this study was to investigate the effects of high-fat diet (HFD) and psychological stress combination on metabolic response to chronic psychological stress in male rats. METHOD: Male Wistar rats were divided into HFD, and normal diet (ND) groups and then into stress and nonstress subgroups. The diets were applied for 5 weeks, and psychological stress was induced for 7 consecutive days. Then, blood samples were taken to measure glucose, insulin, free fatty acids (FFA), and leptin and corticosterone concentrations. Subsequently, glucose-stimulated insulin release from pancreatic isolated islets was assessed. RESULTS: HFD did not significantly change fasting plasma glucose, insulin and corticosterone levels, whereas increased plasma leptin (7.05 ± 0.33) and FFA (p < 0.01) levels and impaired glucose tolerance. Additionally, HFD and stress combination induced more profound glucose intolerance associated with increased plasma corticosterone (p < 0.01) and leptin (8.63 ± 0.38) levels. However, insulin secretion from isolated islets did not change in the presence of high-fat diet and/or stress. CONCLUSION: HFD should be considered as an intensified factor of metabolic impairments caused by chronic psychological stress.

Feed restriction affects milk performances and decreases milk lipolysis in dairy ewes.

Spontaneous lipolysis results in the breakdown of milk fat by the lipoprotein lipase (EC: 3.1.1.34), an enzyme present in milk. Free fatty acids (FFAs) and by-products released in milk during lipolysis can alter both the organoleptic value of milk (off-flavors release) and technological properties of dairy products (decrease in creaming capabilities). Current climate change is having significant impacts on the feeding of grazing animals, with negative consequences on the availability and quality of grass. We and others have demonstrated that dietary restriction increases milk lipolysis in the cow species. However, no data about the impact of feed restriction on milk lipolysis is available in the ewe species. Thus, this paper aims to investigate the effect of feed restriction on milk characteristics with regard to lipolysis values in dairy ewes. Two groups of 24 multiparous Lacaune ewes in mid-lactation received a "non-restricted" control diet (100% of ad libitum DM intake) or a "restricted" (RESTR) diet (65% of ad libitum DM intake) according to a 2 × 2 crossover design. Milk gross composition together with lipolysis analyses were performed. Blood samples were also screened for metabolites or hormone concentrations. The RESTR treatment induced a decrease in milk production (- 21% compared with control treatment) and a modification of the metabolism of dairy ewes characterized by an increase in plasma non-esterified fatty acids (NEFAs), which represents the balance between adipose tissue mobilization and the use of NEFA by other tissues (+153%), cholesterol (+17%) and ß-hydroxybutyrate (+4 %) levels. As a result, a decrease in BW of dairy ewes was observed (-7%). Feed restriction also resulted in a decrease in milk lipolysis estimated by the milk FFA measured by the copper-soap method (-63 and -62%, respectively, for morning and evening milking) or by the reference Bureau of Dairy Industry method (-51 and -57%, respectively, for morning and evening milking). The decrease in milk spontaneous lipolysis under feed restriction was not associated with a decrease in lipoprotein lipase activity in ewes. These results will be completed with proteomic and lipidomic studies in milk samples to better understand mechanisms initiated in the ewe species specifically with regard to lipolysis in milk.

The abnormalities of free fatty acid metabolism in patients with hypertrophic cardiomyopathy, a single-center retrospective observational study.

BACKGROUND: Previous studies have shown the importance of energy deficiency and malfunctioning mitochondria in the pathophysiology of hypertrophic cardiomyopathy (HCM). There has been a little research into the relationship between plasma free fatty acids (FFA), one of the heart's main energy sources, and HCM. We evaluated its clinical importance in HCM to see if there was a link between plasma FFA metabolism and HCM. METHODS: In a single-center retrospective observational study, we investigated 420 HCM patients diagnosed at Beijing Anzhen Hospital between January 1, 2018, and December 31, 2022. Meanwhile, 1372 individuals without HCM (non-HCM) were recruited. 391 non-HCM patients were chosen as controls via a propensity score matching (PSM) study with a 1:1 ratio. RESULTS: FFA in HCM patients showed statistically significant correlations with creatinine (r = 0.115, p = 0.023), estimated GFR (r=-0.130, p = 0.010), BNP (r = 0.152, p = 0.007), LVEF (r=-0.227, p < 0.001), LVFS (r=-0.160, p = 0.002), and LAD (r = 0.112, p = 0.028). Higher FFA levels were found in HCM patients who had atrial fibrillation and NYHY functional classes III or IV (p = 0.015 and p = 0.022, respectively). In HCM patients, multiple linear regression analysis revealed that BNP and LVEF had independent relationships with increasing FFA (Standardized = 0.139, p = 0.013 and =-0.196, p < 0.001, respectively). CONCLUSIONS: Among HCM patients, the plasma FFA concentration was lower, and those with AF and NYHY functional class III or IV had higher FFA levels, and LVEF and BNP were independently associated with increasing FFA. The findings of the study should help inspire future efforts to better understand how energy deficiency contributes to hypertrophic cardiomyopathy (HCM) development.

Variations of blood metabolites in single- and multiple-bearing Ossimi ewes during the transition period.

Evaluation of the metabolic profile indices allows early detection and treatment of various metabolic disorders during the transition period in ewes. This study aimed to determine the variations in the blood metabolites around lambing in Ossimi ewes. The blood metabolites were investigated in ewes with single (n = 27) and multiple (n = 9) lambs at 3- and 1-week pre-lambing and 3-week post-lambing. The plasma concentrations of glucose were higher in single-bearing ewes than those in multiple-bearing ewes (p < .05), moreover, its lowest value was measured at 1-week prepartum in both groups. Throughout the study period, the serum concentrations of non-esterified fatty acids (NEFA) were significantly increased in ewes with multiple lambs compared to ewes with single lambs (p < .05), and the highest value was found at 1-week before parturition in both groups. In addition, the serum level of beta-hydroxybutyric acid (BHBA) was higher at 3-week postpartum, and it was significantly increased in multiple-bearing ewes than that in single-bearing ones (p < .05) at 3-week pre-lambing. In both groups, the lowest values of total proteins were determined 1-week before lambing, and its concentrations, at 3- and 1-week prepartum, were higher in ewes with single lambs than those with multiple lambs (p < .05). In contrast, the serum concentrations of albumin were significantly lowered 1-week postpartum (p < .05), and without significant differences between both groups (p > .05). The serum activities of aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) were significantly increased at 1-week after parturition in both groups (p < .05). Furthermore, the serum activities of AST were higher in multiple-bearing ewes than those in single-bearing ones at 3-week pre-lambing and 3-week post-lambing (p < .05). Variable positive and negative correlations were determined among the blood metabolites. In conclusion, physiological adaptations are associated with the fluctuation of the blood metabolites around lambing. The higher the number of foetuses the higher the metabolic variations in Ossimi ewes. Therefore, regular metabolic profiling for health monitoring may be necessary to avoid disease development during the transition period.

[Relationship between body condition of dairy cows in the peripartum period and selected metabolic parameters in consideration of different breeds]. / Zusammenhänge zwischen Körperkondition von Milchkühen im peripartalen Zeitraum und ausgewählten Stoffwechselparametern unter Berücksichtigung verschiedener Rassen.

OBJECTIVE: The results of this study describe the relationship between the body condition of dairy cows and selected metabolic parameters during the peri- and post-partum period with special consideration of 3 local dairy cow breed in Upper Bavaria and the Allgau. MATERIAL AND METHODS: Three local dairy cattle breeds (Swiss Brown (BV), Simmental (FL), Holstein Friesian (HF)) were examined on 68 farms in southern Germany for 7 consecutive weeks. In dry cows as well as lactating cows (5.-65. day in milk), following blood parameters were investigated: beta-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA), creatinine, aspartate aminotransferase, gamma-glutamyltransferase, glutamate dehydrogenase, total protein, albumin, creatine kinase. In addition, body condition (body condition score [BCS] and back fat thickness [BFT]) were recorded. Exploratory and descriptive statistics were used for data analysis. RESULTS: Concerning the difference in condition before and after calving, the FL showed the smallest difference in RFD. For FL and BV a trend towards higher BFT values could be seen in first lactating cows. For FL and HF, the NEFA values of the later lactating cows were below those of the first lactating cows. The higher lactating cows of BV and FL had higher BHB values. The correlation between BFT and BCS showed the highest R2 (0.53) in the HF cows. BV and FL were below at 0.42 and 0.37. BCS and BFT could not be predicted by the variables NEFA, BHB and liver enzymes. BHB levels of all 3 breeds increased at weeks 2-4 post-partum. The NEFA values for all 3 breeds increased primarily in the 1st-3rd week p.p. in parallel to when the BFT p.p. decreased. NEFA values were highest when body condition declined and therefore when fat mobilization peaked. In BV and HF, there was a constant increase in GLDH when the p.p. BCS difference was there. CONCLUSION AND CLINICAL RELEVANCE: Body condition assessment (BCS at herd and animals` level, BFT at animal level) is an important tool for animal health monitoring. Due to the recognizable breed specificity, the dairy herds can be dealt with more explicitly. The aim is to optimally influence the energy balance of the cow during early lactation in order maintain the health of the animal and its organ systems.

Deficits in brain glucose transport among younger adults with obesity.

OBJECTIVE: Obesity is associated with alterations in eating behavior and neurocognitive function. In this study, we investigate the effect of obesity on brain energy utilization, including brain glucose transport and metabolism. METHODS: A total of 11 lean participants and 7 young healthy participants with obesity (mean age, 27 years) underwent magnetic resonance spectroscopy scanning coupled with a hyperglycemic clamp (target, ~180 mg/dL) using [1-13C] glucose to measure brain glucose uptake and metabolism, as well as peripheral markers of insulin resistance. RESULTS: Individuals with obesity demonstrated an ~20% lower ratio of brain glucose uptake to cerebral glucose metabolic rate (Tmax/CMRglucose) than lean participants (2.12 ± 0.51 vs. 2.67 ± 0.51; p = 0.04). The cerebral tricarboxylic acid cycle flux (VTCA) was similar between the two groups (p = 0.64). There was a negative correlation between total nonesterified fatty acids and Tmax/CMRglucose (r = -0.477; p = 0.045). CONCLUSIONS: We conclude that CMRglucose is unlikely to differ between groups due to similar VTCA, and, therefore, the glucose transport Tmax is lower in individuals with obesity. These human findings suggest that obesity is associated with reduced cerebral glucose transport capacity even at a young age and in the absence of other cardiometabolic comorbidities, which may have implications for long-term brain function and health.

Development and application of a sensitive liquid chromatography-tandem mass spectrometry method for the quantitative analysis of 11 free fatty acids in human serum using a derivatisation strategy.

A stable isotope dilution-liquid chromatography-tandem mass spectrometry method based on a derivatisation strategy involving an N,N'-carbonylimidazole solution (CDI) with 4-(dimethylamino)-benzenemethanamine was developed for the determination of 11 free fatty acids (FFAs) in human blood samples. Serum samples were subjected to liquid‒liquid extraction and centrifuged, and the supernatant was collected for a two-step derivatisation reaction with a CDI and 4-(dimethylamino)-aniline acetonitrile solution. The derivatised solution was separated on a ACQUITY UPLC HSS T3 column (2.1 × 50 mm, 1.8 µm) column with a mobile phase consisting of water-acetonitrile in gradient elution and then detected by tandem mass spectrometry using electrospray ionisation (ESI) and multiple reaction monitoring (MRM) in positive ion mode and quantified using the isotope internal standard method. The effects of the derivatisation reaction time, temperature and concentration of derivatisation reagents on the response values of the analytes were investigated. The optimal conditions were as follows: 1.0 mg mL-1 CDI acetonitrile solution at 25 °C for 25 min, followed by a reaction with a 1.0 mg mL-1 4-(dimethylamino)-benzenemethanamine acetonitrile solution at 70 °C for 30 min. Under the optimal conditions, the limits of detection (LODs) of the 11 FFAs were in the range of 3.0-14.0 ng mL-1; the limits of quantification (LOQs) were in the range of 8.0-45.0 ng mL-1; and the mean recoveries ranged from 83.4 to 112.8%, with intraday and interday precisions ranging from 0.7 to 9.1% and 3.7-9.5%, respectively. The experimental method is simple in terms of the pretreatment operation, accurate and reliable, and can be applied to the sensitive determination of FFAs in human blood samples.

Insulin resistance in the adipose tissue predicts future vascular resistance: The Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases.

BACKGROUND AND AIMS: Diameter, plaque score, and resistance index (RI) in the common carotid artery (CCA) are indicators of arterial remodeling, atherosclerosis, and vascular resistance, respectively. This study investigated the longitudinal association between adipose tissue insulin resistance or serum free fatty acid (FFA) levels and the CCA parameters. METHODS: This retrospective cohort analysis included 1089 participants (mean age 57.6 years; 40.0 % women) with data on health checkups from January 1982 to March 2003 and carotid artery ultrasonography from January 2015 to June 2019. Baseline serum FFA and immunoreactive insulin levels were assessed before and 30, 60, and 120 min after glucose ingestion. Adipose insulin resistance index (Adipo-IR) was calculated as the product of fasting serum insulin and FFA levels. An RI value >0.75 was defined as high RI. RESULTS: A significant association was found between Adipo-IR and RI; however, Adipo-IR showed no association with CCA diameter or plaque score. The incidence of high RI increased with Adipo-IR quartile (Q) groups (47.3 % in Q1, 52.8 % in Q2, 53.3 % in Q3, 62.4 % in Q4; Cochrane-Armitage test for trend, p < 0.001). In multivariate analysis, Adipo-IR levels (Q4 vs. Q1 odds ratio: 1.67, 95 % confidence interval: 1.12-2.51) were positively associated with high RI incidence. Moreover, a significant association was found between RI and serum FFA levels after glucose intake, but not fasting FFA levels. CONCLUSIONS: Future vascular resistance was predicted by insulin resistance in the adipose tissue. After glucose intake, serum FFA levels may significantly impact vascular resistance development.

Effects of Dietary Carbohydrate Concentration and Glycemic Index on Blood Glucose Variability and Free Fatty Acids in Individuals with Type 1 Diabetes.

Monitoring glycemic control status is the cornerstone of diabetes management. This study aimed to reveal whether moderate-carbohydrate (CHO) diets increase the risk of free fatty acid (FFA) levels, and it presents the short-term effects of four different diet models on blood sugar, glycemic variability (GV), and FFA levels. This crossover study included 17 patients with type 1 diabetes mellitus to identify the effects of four diets with different CHO contents and glycemic index (GI) on GV and plasma FFA levels. Diet 1 (D1) contained 40% CHO with a low GI, diet 2 (D2) contained 40% CHO with a high GI, diet 3 (D3) contained 60% CHO with a low GI, and diet 4 (D4) contained 60% CHO with a high GI. Interventions were performed with sensor monitoring in four-day periods and completed in four weeks. No statistical difference was observed among the groups in terms of blood glucose area under the curve (p = 0.78), mean blood glucose levels (p = 0.28), GV (p = 0.59), and time in range (p = 0.567). FFA and total triglyceride levels were higher in the D1 group (p < 0.014 and p = 0.002, respectively). Different diets may increase the risk of cardiovascular diseases by affecting GI, FFA, and blood glucose levels.

Effects of acute and chronic stair-climbing exercise on metabolic health: A systematic review.

Stair climbing exercise (SE) provides a feasible approach to elevate physical activity, but the effects on metabolic health are unclear. We systematically reviewed the currently available evidence on the effects of SE on fasting and postprandial glycaemia and lipidaemia. Studies were included if they investigated the effects of acute or chronic (at least 2 weeks) SE on fasting and/or postprandial glycaemic (insulin and glucose) and lipidaemic (triacylglycerols and non-esterified fatty acids) responses in healthy, prediabetic or type 2 diabetic adult populations. PubMed, Web of Science and Scopus were searched for eligible studies until July 2022. A total of 25 studies (14 acute and 11 chronic) were eligible for review. Acute bout(s) of SE can reduce postprandial glycaemia in individuals with prediabetes and type 2 diabetes (8 of 9 studies), but not in normoglycemic individuals. The effects of acute SE on postprandial lipidaemic responses and SE training on both fasting and postprandial glycaemia/lipidaemia were unclear. Acute SE may reduce postprandial glucose concentrations in people with impaired glycaemic control, but high-quality studies are needed. More studies are needed to determine the effect of chronic SE training on postprandial glucose and lipid responses, and the acute effects of SE on lipid responses.

Analysis of correlative factors of female coronary slow-flow phenomenon: A retrospective study.

The coronary slow-flow phenomenon (CSFP) is a manifestation of coronary artery disease wherein coronary angiography reveals no apparent stenosis; however, there is a delay in blood flow perfusion. Given its increased occurrence in male patients, with the majority of subjects in previous studies being male, this study aimed to explore whether distinct risk factors are present in female patients with CSFP. This single-center retrospective study focused on female patients diagnosed with CSFP by using coronary angiography. Eligible patients meeting the predefined inclusion and exclusion criteria were divided into the study group (presenting with CSFP) and control group (displaying normal epicardial coronary arteries). Comparative analyses of clinical and diagnostic data were performed. Ninety-two patients with CSFP and an equal number of controls were enrolled in this study. Patients with CSFP exhibited a higher prevalence of smokers (P = .017) and a heightened incidence of diabetes mellitus (DM) (P = .007). Significantly elevated levels of total cholesterol (TC) (P = .034) and free fatty acids (FFA) (P = .016) were observed in the CSFP group compared to those in the control group. Additionally, patients with CSFP displayed lower levels of apolipoprotein E (ApoE) (P = .092), free thyroxine (FT4) (P = .001), and total thyroxine (TT4) (P = .025). Logistic regression analysis indicated that smoking (P = .019), FFA (P < .001), ApoE (P = .015), and FT4 (P < .001) were independent risk factors for CSFP, accounting for confounding factors. Additionally, the area under the ROC curve (AUC) of the combined effect of smoking, ApoE, FT4, and FFA on CSFP was 0.793 (95% CI: 0.729-0.857, P < .01). In addition to the established risk factors for smoking, diabetes, and hyperlipidemia, female patients with CSFP exhibited significant differences in apoE, FFA, FT4, and TT4 levels compared to the control group. Smoking, FFA, and FT4 levels emerged as independent risk factors for CSFP.

Heat stress alters hematological parameters in barrows and gilts.

The purpose of this investigation was to establish the role biological sex plays in circulating factors following heat stress (HS). Barrows and gilts (36.8 ±â€…3.7 kg body weight) were kept in either thermoneutral (TN; 20.8 ±â€…1.6 °C; 62.0% ±â€…4.7% relative humidity; n = 8/sex) conditions or exposed to HS (39.4 ±â€…0.6 °C; 33.7% ±â€…6.3% relative humidity) for either 1 (HS1; n = 8/sex) or 7 (HS7; n = 8/sex) d. Circulating glucose decreased as a main effect of the environment (P = 0.03). Circulating non-esterified fatty acid (NEFA) had an environment × sex interaction (P < 0.01) as HS1 barrows had increased NEFA compared to HS1 gilts (P = 0.01) and NEFA from HS7 gilts increased compared to HS1 gilts (P = 0.02) and HS7 barrows (P = 0.04). Cortisol, insulin, glucagon, T3, and T4 were reduced as a main effect of environment (P ≤ 0.01). Creatinine was increased in HS1 and HS7 animals compared to TN (P ≤ 0.01), indicative of decreased glomerular filtration rate. White blood cell populations exhibited differential patterns based on sex and time. Neutrophils and lymphocytes had an environment × sex interaction (P ≤ 0.05) as circulating neutrophils were increased in HS1 barrows compared to TN and HS7 barrows, and HS1 gilts (P ≤ 0.01) and HS7 barrows had less neutrophils compared to TN barrows (P = 0.01), whereas they remained similar in gilts. In contrast, barrow lymphocyte numbers were similar between groups, but in HS7 gilts they were decreased compared to TN and HS1 gilts (P ≤ 0.04). In total, these data demonstrate that HS alters a host of circulating factors and that biological sex mediates, at least in part, the physiological response to HS.

Heat stress (HS) negatively impacts efficient pork production; however, the role of biological sex is largely unknown. The objective of this study was to determine the extent to which HS differentially impacted hematological parameters in barrows and gilts. To address this, 3-mo-old barrows and gilts were exposed to ambient temperature (TN) or constant HS for 1 or 7 d. Following the experimental period, blood was collected for analysis of hormones, metabolites, immune cells, and markers of organ damage. Overall, cortisol, insulin, glucagon, T3, and T4 were reduced following HS. Furthermore, 7 d of HS decreased circulating glucose, albeit slightly. Circulating fatty acids had a sex-specific response as HS1 barrows and HS7 gilts were increased compared to their environmental counterparts, though, these changes are minor compared to those expected with a similar feed restriction. HS caused immune system activation in barrows and gilts; however, circulating levels of specific white blood cells were time- and sex-dependent. Barrows appeared more resistant to HS-mediated kidney injury acutely; however, with continued heating, markers of kidney injury were similar between barrows and gilts. In total, these data suggest biological sex regulates some, but not all, aspects of HS-mediated biological changes in pigs.

High-fat diet consumption promotes adolescent neurobehavioral abnormalities and hippocampal structural alterations via microglial overactivation accompanied by an elevated serum free fatty acid concentration.

Mounting evidence suggests that high-fat diet (HFD) consumption increases the risk for depression, but the neurophysiological mechanisms involved remain to be elucidated. Here, we demonstrated that HFD feeding of C57BL/6J mice during the adolescent period (from 4 to 8 weeks of age) resulted in increased depression- and anxiety-like behaviors concurrent with changes in neuronal and myelin structure in the hippocampus. Additionally, we showed that hippocampal microglia in HFD-fed mice assumed a hyperactive state concomitant with increased PSD95-positive and myelin basic protein (MBP)-positive inclusions, implicating microglia in hippocampal structural alterations induced by HFD consumption. Along with increased levels of serum free fatty acids (FFAs), abnormal deposition of lipid droplets and increased levels of HIF-1α protein (a transcription factor that has been reported to facilitate cellular lipid accumulation) within hippocampal microglia were observed in HFD-fed mice. The use of minocycline, a pharmacological suppressor of microglial overactivation, effectively attenuated neurobehavioral abnormalities and hippocampal structural alterations but barely altered lipid droplet accumulation in the hippocampal microglia of HFD-fed mice. Coadministration of triacsin C abolished the increases in lipid droplet formation, phagocytic activity, and ROS levels in primary microglia treated with serum from HFD-fed mice. In conclusion, our studies demonstrate that the adverse influence of early-life HFD consumption on behavior and hippocampal structure is attributed at least in part to microglial overactivation that is accompanied by an elevated serum FFA concentration and microglial aberrations represent a potential preventive and therapeutic target for HFD-related emotional disorders.

Increased molar ratio of free fatty acids to albumin in blood as cause and early biomarker for the development of cataracts and Alzheimer's disease.

Cataracts and Alzheimer's disease (AD) are closely linked and are associated with aging and with systemic diseases that increase the molar ratio of free fatty acids to albumin (mFAR) in the blood. From the results of our earlier studies on the development of senile cataracts and from results recently published in the literature on the pathogenesis of Alzheimer's disease, we suggest that there is a common lipotoxic cascade for both diseases, explaining the strong connection between aging, an elevated mFAR in the blood, cataract formation, and AD. Long-chain free fatty acids (FFA) are transported in the blood as FFA/albumin complexes. In young people, vascular albumin barriers in the eyes and brain, very similar in their structure and effect, reduce the FFA/albumin complex concentration from around 650 µmol/l in the blood to 1-3 µmol/l in the aqueous humour of the eyes as well as in the cerebrospinal fluid of the brain. At such low concentrations the fatty acid uptake of the target cells - lens epithelial and brain cells - rises with increasing FFA/albumin complex concentrations, especially when the fatty acid load of albumin molecules is mFAR>1. At higher albumin concentrations, for instance in blood plasma or the interstitial tissue spaces, the fatty acid uptake of the target cells becomes increasingly independent of the FFA/albumin complex concentration and is mainly a function of the mFAR (Richieri et al., 1993). In the blood plasma of young people, the mFAR is normally below 1.0. In people over 40 years old, aging increases the mFAR by decreasing the plasma concentration of albumin and enhancing the plasma concentrations of FFA. The increase in the mFAR in association with C6-unsaturated FFA are risk factors for the vascular albumin barriers (Hennig et al., 1984). Damage to the vascular albumin barrier in the eyes and brain increases the concentration of FFA/albumin complex in the aqueous humour as well as in the cerebrospinal fluid, leading to mitochondrial dysfunction and the death of lens epithelial and brain cells, the development of cataracts, and AD. An age-dependent increase in the concentration of FFA/albumin complex has been found in the aqueous humour of 177 cataract patients, correlating with the mitochondria-mediated apoptotic death of lens epithelial cells, lens opacification and cataracts (Iwig et al., 2004). Mitochondrial dysfunction is also an early crucial event in Alzheimer's pathology, closely connected with the generation of amyloid beta peptides (Leuner et al., 2012). Very recently, amyloid beta production has also been confirmed in the lenses of Alzheimer's patients, causing cataracts (Moncaster et al., 2022). In view of this, we propose that there is a common lipotoxic cascade for senile cataract formation and senile AD, initiated by aging and/or systemic diseases, leading to an mFAR>1 in the blood.

Adipocyte PI3K links adipostasis with baseline insulin secretion at fasting through an adipoincretin effect.

Insulin-PI3K signaling controls insulin secretion. Understanding this feedback mechanism is crucial for comprehending how insulin functions. However, the role of adipocyte insulin-PI3K signaling in controlling insulin secretion in vivo remains unclear. Using adipocyte-specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we show that PI3Kα and PI3Kß activities are functionally redundant in adipocyte insulin signaling. PI3Kß-selective inhibitors have no effect on adipocyte AKT phosphorylation in control mice but blunt it in adipocytes of PI3KαAdQ mice, demonstrating adipocyte-selective pharmacological PI3K inhibition in the latter. Acute adipocyte-selective PI3K inhibition increases serum free fatty acid (FFA) and potently induces insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect operates in fasted mice with increasing FFA and decreasing glycemia, indicating that it is not primarily a control system for blood glucose. This feedback control system defines the rates of adipose tissue lipolysis and chiefly controls basal insulin secretion during fasting.

Insulin regulation of regional lipolysis in upper-body obese and lean humans.

BACKGROUND: Upper-body obesity (UBO) results in insulin resistance with regards to free fatty acid (FFA) release; how this differs by fat depot and sex between adults with UBO and lean adults is unknown. We tested the hypothesis that insulin suppression of FFA release from the splanchnic bed, leg fat, and upper-body nonsplanchnic (UBNS) adipose tissue would be impaired in UBO. METHODS: Fourteen volunteers with UBO (7 men and 7 women) and 14 healthy volunteers with normal weight (7 men and 7 women) participated in studies that included femoral artery, femoral vein, and hepatic vein catheterization. We then measured leg and splanchnic plasma flow as well as FFA kinetics (using isotopic tracers) under overnight fasting as well as low- and high-dose insulin infusion using the insulin clamp technique. RESULTS: We found the expected insulin resistance in UBO; the most quantitatively important difference between adults with UBO and lean adults was greater FFA release from UBNS adipose tissue when plasma insulin concentrations were in the postprandial, physiological range. There were obesity, but not sex, differences in the regulation of splanchnic FFA release and sex differences in the regulation of leg FFA release. CONCLUSION: Reversing the defects in insulin-regulated UBNS adipose tissue FFA release would have the greatest effect on systemic FFA abnormalities in UBO. FUNDING: These studies were supported by the US Public Health Service (grants DK45343 and DK40484), the Novo Nordic Foundation (grant NNF18OC0031804 and NNF16OC0021406), and the Independent Research Fund Denmark (grant 8020-00420B).