Lean Controls Research Articles

Reduced Striatal Dopamine Transporter Availability and Heightened Response to Natural and Pharmacological Stimulation in CCK-1R-Deficient Obese Rats.

Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control Long-Evans Tokushima (LETO) rats, OLETF rats have pronounced avidity for over-consuming palatable sweet solutions, have greater dopamine release to psychostimulants, reduced dopamine 2 receptor (D2R) binding, and exhibit increased sensitivity to sucrose reward. This supports altered dopamine function in this strain and its general preference for palatable solutions such as sucrose. In this study, we examined the relationship between OLETF's hyperphagic behavior and striatal dopamine signaling by investigating basal and amphetamine stimulated motor activity in prediabetic OLETF rats before and after access to sucrose solution (0.3 M) compared to non-mutant control LETO rats, as well as availability of dopamine transporter (DAT) using autoradiography. In the sucrose tests, one group of OLETF rats received ad libitum access to sucrose while the other group received an amount of sucrose equal to that consumed by the LETO. OLETFs with ad libitum access consumed significantly more sucrose than LETOs. Sucrose exerted a biphasic effect on basal activity in both strains, i.e., reduced activity for 1 week followed by increased activity in weeks 2 and 3. Basal locomotor activity was reduced (-17%) in OLETFs prior to sucrose, compared to LETOs. Withdrawal of sucrose resulted in increased locomotor activity in both strains. The magnitude of this effect was greater in OLETFs and the activity was increased in restricted compared to ad-libitum-access OLETFs. Sucrose access augmented AMPH-responses in both strains with a greater sensitization to AMPH during week 1, an effect that was a function of the amount of sucrose consumed. One week of sucrose withdrawal sensitized AMPH-induced ambulatory activity in both strains. In OLETF with restricted access to sucrose, withdrawal resulted in no further sensitization to AMPH. DAT availability in the nucleus accumbens shell was significantly reduced in OLETF compared with aged-matched LETO. Together, these findings show that OLETF rats have reduced basal DA transmission and a heightened response to natural and pharmacological stimulation.

P446 INDEPENDENT EFFECTS OF TYPE 2 DIABETES AND OBESITY ON CARDIOPULMONARY PERFORMANCE IN SUBJECTS AT HIGH CARDIOVASCULAR RISK

Abstract Background Both obesity and type 2 diabetes (T2D) are associated with effort intolerance and heart failure. Since the two conditions often coexist and overlap, their distinct effect on cardiopulmonary performance remains to be elucidated. Methods Patients at high cardiovascular risk, free from any clinical or instrumental evidence of heart disease, with a wide range of body mass index (BMI) values, and with or without T2D underwent combined echocardiography–cardiopulmonary exercise test (eCPET). Patients were divided in T2D and controls, as well as in lean (BMI <25 kg/m2), overweight (BMI 25 – 30 kg/m2), and obese (BMI >30 kg/m2). Results A total of 206 patients was analyzed, divided in 109 patients with T2D and 97 controls. Increased BMI is associated with multiple cardiovascular dysfunctions including chronotropic insufficiency, subclinical systolic dysfunction (reduced global longitudinal strain, GLS), and impaired systolic reserve, achieving significantly lower oxygen uptake and workload. Obesity is associated with reduced lung volumes and mild ventilatory alterations at peak exercise, irrespective of diabetes. T2D patients showed more frequent LV concentric remodeling, worse systolic and diastolic performance at rest with diminished ameliorations during exercise, and worse sympatho–vagal balance as expressed by the higher prevalence of chronotropic insufficiency and delayed heart rate recovery. Nonetheless, when divided in BMI subclasses, the differences between T2D and controls were only evident among lean subjects. In fact, while no difference between T2D and controls was evident among overweight and obese patients, lean individuals with T2D display worse cardiopulmonary performance than lean controls, achieving lower workload and lower VO2peak, revealing systolic dysfunction (lower GLS) and higher LV filling pressures (E/e’). Unlike glycated hemoglobin, strong linear relationships were proven between fat mass and oxygen uptake, workload, systolic, and diastolic indices. Conclusions T2D affects LV dimensions and geometry, systo–diastolic functions, autonomic balance, cardiopulmonary capacity, and exercise tolerance, independently of the presence of obesity. Nonetheless, increased BMI is an even more powerful independent negative determinant of systolic function, autonomic balance, and effort tolerance. These early alterations might partly explain the increased risk of developing heart failure associated with diabetes and obesity.

Calorie restriction and pravastatin administration during pregnancy in obese rhesus macaques modulates maternal and infant metabolism and infant brain and behavioral development.

Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development. A total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods. Gestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test. Although the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.

Influence of bariatric surgery on the peripheral blood immune system of female patients with morbid obesity revealed by high-dimensional mass cytometry.

Obesity is associated with low-grade chronic inflammation, altered levels of adipocytokines, and impaired regulation of gastrointestinal hormones. Secreted, these factors exert immunostimulatory functions directly influencing peripheral immune cells. In the realm of this study, we aimed to investigate the composition and activation status of peripheral blood immune cells in female patients with morbid obesity compared to lean controls using high-dimensional mass cytometry. Besides, we also assessed the influence of bariatric surgery with respect to its ability to reverse obesity-associated alterations within the first-year post-surgery. Patients with morbid obesity showed typical signs of chronic inflammation characterized by increased levels of CRP and fibrinogen. Apart from that, metabolic alterations were characterized by increased levels of leptin and resistin as well as decreased levels of adiponectin and ghrelin compared to the healthy control population. All these however, except for ghrelin levels, rapidly normalized after surgery with regard to control levels. Furthermore, we found an increased population of monocytic CD14+, HLA-DR-, CD11b+, CXCR3+ cells in patients with morbid obesity and an overall reduction of the HLA-DR monocytic expression compared to the control population. Although CD14+, HLA-DR-, CD11b+, CXCR3+ decreased after surgery, HLA-DR expression did not recover within 9 - 11 months post-surgery. Moreover, compared to the control population, patients with morbid obesity showed a perturbed CD4+ T cell compartment, characterized by a strongly elevated CD127+ memory T cell subset and decreased naïve T cells, which was not recovered within 9 - 11 months post-surgery. Although NK cells showed an activated phenotype, they were numerically lower in patients with morbid obesity when compared to healthy controls. The NK cell population further decreased after surgery and did not recover quantitatively within the study period. Our results clearly demonstrate that the rapid adaptions in inflammatory parameters and adipocytokine levels that occur within the first year post-surgery do not translate to the peripheral immune cells. Apart from that, we described highly affected, distinct immune cell subsets, defined as CD127+ memory T cells and monocytic CD14+, HLA-DR, CD11b+, CXCR3+ cells, that might play a significant role in understanding and further decoding the etiopathogenesis of morbid obesity.

Ovarian-derived sex hormones do not mediate the sex-specific mechanism of hypertension in obese mice

The longstanding dogma that female sex hormones protect premenopausal women against cardiovascular disease perpetuated the belief that sex hormones are the main determinant for cardiovascular risk. However, increasing global trends for obesity and recent clinical evidence indicate that obesity abrogates the protective effects of female sex and predisposes women to vascular dysfunction and hypertension. Previously, our laboratory demonstrated that obesity-associated hypertension manifests via sex-specific mechanisms: leptin-mediated sympatho-activation in males and leptin-mediated aldosterone production in females. Whether sex hormones are the source for these sex differences remains unknown. We hypothesized that loss of ovarian-derived sex hormones with ovariectomy (OVX) will alter the mechanism by which obese female mice develop hypertension and impair vascular function. Obese agouti yellow mice and lean controls underwent OVX or sham surgery at 12 weeks. At 15 weeks of age, mice were implanted with radiotelemeters to record blood pressure (BP) at baseline and in response to leptin receptor blockade (Allo-Aca, 0.05mg/kg/day s.c. osmotic minipump). To determine the effect of OVX on autonomic control of BP, we recorded BP and heart rate (HR) responses to ganglionic blockade, muscarinic and β-adrenergic receptor antagonists. At 18 weeks, mice were euthanized and mesenteric arteries isolated to measure vascular function via wire myography. Obesity significantly increased (2-way ANOVA, P<0.05) mean arterial pressure (MAP), systolic BP, diastolic BP, and HR but surprisingly OVX did not further elevate BP. However, leptin receptor blockade significantly decreased (2-way ANOVA, P<0.05) MAP in obese mice, indicating that BP elevation remains leptin-dependent in OVX obese female mice. OVX did not alter MAP or HR responses to ganglionic blockade, muscarinic and β-adrenergic receptor antagonists, suggesting no further contribution of autonomic control of BP. Mesenteric wire myography revealed obesity significantly impaired (2-way ANOVA, P<0.05) endothelial-dependent relaxation to acetylcholine but interestingly, loss of ovarian-derived sex hormones did not cause further impairment. Western blot analysis showed no alteration in adrenal aldosterone synthase expression in obese OVX mice and LC-MS revealed no difference in plasma aldosterone levels. These results indicate that in the absence of ovarian-derived female sex hormones, hypertension remains leptin-dependent and aldosterone-mediated in obese female mice and female sex steroids likely play a limited role. This work challenges the notion that sex hormones mediate the sex-specific mechanism of hypertension in the context of obesity suggesting sex chromosomes as the underlying origin for the difference in mechanism. R01HL130301, R01HL155265 (E.J.B.) T32 HL155011-01A1 (C.T.B.) This is the full abstract presented at the American Physiology Summit 2023 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.

High fat-high sugar diet induces sex-dependent effects on the small intestine

Background: Metabolic syndrome includes a plethora of symptoms ultimately leading to obesity and type 2 diabetes. Obesity has been linked to chronic gastrointestinal dysfunction (constipation, or diarrhea) and specifically females with high BMI have been associated with increased prevalence of diarrhea. We aimed to better understand the influence of high fat-high sugar diet (Western diet) on small intestinal function and to assess sex-dependent effects. Methods: We measured transepithelial short circuit current (Isc) a measure of chloride secretory function, across freshly isolated segments of jejunum from male and female C57Bl/6J mice fed a high fat high sugar diet (HFS) for 12 weeks, compared to lean controls. At the completion of the study, segments of jejunum were frozen for western blot determination of key proteins involved in secretory and absorptive functions and senescence. Intestinal morphology was assessed. Serum cytokine assays were performed. Results: Basal Isc was significantly decreased 70% ( P<0.05) in HFS both females and males versus leans. In females, the HFS-induced decrease in Isc was attributed to a significant loss of CLC2, NKCC1 and CFTR expression whereas in males the decrease in Isc was due to a significant loss of Na/K-ATPase, KCa and NKCC1 expression (indicating interesting sex-dependent etiology). A2BR levels were also dysregulated in HFS fed male and female mice. Inflammatory state and shadowed body weight changes with feeding a western diet. Assessment of intestinal morphology and metabolic profile is being further evaluated. Conclusions: Our data suggests that the reduced basal jejunal Isc in HFS mice is attributed to sex-dependent mechanisms. Improved understanding of Western diet-induced intestinal dysfunctions may provide improved drug targets to treat gastrointestinal disturbances in obesity and diabetes. Midwestern Arizona Alzheimer’s Consortium and Diabetes Action Research and Education Foundation This is the full abstract presented at the American Physiology Summit 2023 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.

Neutrophil peptidylarginine deiminase 4 plays a systemic role in obesity-induced chronic inflammation in mice

Abstract Obesity is an increasing problem in our current society. In morbidly obese patients, the level of circulating neutrophil extracellular traps (NETs) was found to be higher than in lean control subjects. Essential in this process of NET formation is the activation of the enzyme peptidylarginine deiminase 4 (PAD4). We aimed to understand how NETs contribute to the detrimental effects associated with a prolonged state of (morbid) obesity. Therefore, an animal model was adopted in which wild type (WT) and neutrophil specific PAD4 deficient (Ne-PAD4 −/−) mice on a C57BL6/J background were fed a high fat containing diet (HFD – 60kcal% fat) for a period of 10 weeks. Neutrophil activation status, evaluated through the formation of NETs in response to calcium ionophore ionomycin (4 μM) stimulation, was initially reduced after 3 days of HFD feeding. At later timepoints (5- and 10-weeks), neutrophils isolated from HFD-fed mice showed increased levels of NET formation in response to ionomycin stimulation in comparison to neutrophils from control diet-fed mice. Ne-PAD4 −/−mice on the HFD gained less weight than WT mice, which had a constant gain of body weight over the 10-week experimental period. Finally, after 10-weeks of high fat intake, cardiac function was evaluated in WT and Ne-PAD4 −/−mice by echocardiography. Interestingly, in WT mice diastolic function (early passive vs late active filling, E/A ratio) decreased as compared to baseline values, while Ne-PAD4 −/−mice kept E/A ratios comparable to baseline levels. Here, we demonstrate the importance of systemic NET release under metabolic challenge, and how this can contribute to cardiac deterioration at a young age due to obesity-induced alteration in the innate immune system.

Waist circumference mediates the association between rs1260326 in GCKR gene and the odds of lean NAFLD

While non-alcoholic fatty liver disease (NAFLD) has been widely studied, the pathophysiology of lean NAFLD, the critical NAFLD subgroup, remains elusive. This study aimed to clarify the association between polymorphisms of GCKR, waist circumference, and the odds of lean NAFLD in the elderly Chinese Han population who live in the Zhangjiang community center of Shanghai, China. Three single nucleotide polymorphisms (SNPs), including rs1260326, rs780093, and rs780094, were genotyped in MassARRAY Analyzer. The association between SNPs with waist circumference in five genetic models was analyzed and rechecked by the logistic regression analysis. Mediation models were established to evaluate whether the waist circumstance can mediate the association between SNPs and lean NAFLD. In this study, the frequency of the C allele of rs1260326, rs780093, and rs780094 was significantly lower in lean NAFLD individuals than in lean non-NAFLD ones. The association between rs1260326 in GCKR and the odds of lean NAFLD was mediated via waist circumference after adjusting gender and age in the elderly Chinese Han population (β = 1.196, R2 = 0.043, p = 0.020). For the first time, this study examined the mediating effect of waist circumference on the association between rs1260326 in GCKR and the odds of lean NAFLD (β = 0.0515, 95% CI 0.0107–0.0900, p = 0.004). It may contribute to illustrating the pathogenesis of lean NAFLD and indicate that waist circumference management might improve lean NAFLD control.

Acute exercise increases the contact between lipid droplets and mitochondria independently of obesity and type 2 diabetes.

Intramuscular lipid droplets (LDs) and mitochondria are essential organelles in cellular communication and metabolism, supporting local energy demands during muscle contractions. While insulin resistance impacts cellular functions and systems within the skeletal muscle, it remains unclear whether the interaction of LDs and mitochondria is affected by exercise and the role of obesity and type 2 diabetes. By employing transmission electron microscopy (TEM), we aimed to investigate the effects of 1h of ergometry cycling on LD morphology, subcellular distribution and mitochondrial contact in skeletal muscle fibres of patients with type 2 diabetes and glucose-tolerant lean and obese controls, matched for equal exercise intensities. Exercise did not change LD volumetric density, numerical density, profile size or subcellular distribution. However, evaluated as the magnitude of inter-organelle contact, exercise increased the contact between LDs and mitochondria with no differences between the three groups. This effect was most profound in the subsarcolemmal space of type 1muscle fibres, and here the absolute contact length increased on average from ∼275 to ∼420nm. Furthermore, the absolute contact length before exercise (ranging from ∼140 to ∼430nm) was positively associated with the fat oxidation rate during exercise. In conclusion, we showed that acute exercise did not mediate changes in the LD volume fractions, numbers or size but increased the contact between LDs and mitochondria, irrespective of obesity or type 2 diabetes. These data suggest that the increased LD-mitochondria contact with exercise is not disturbed in obesity or type 2 diabetes. KEY POINTS: Type 2 diabetes is associated with altered interactivity between lipid droplets (LDs) and mitochondria in the skeletal muscle. Physical contact between the surface of LDs and the surrounding mitochondrial network is considered favourable for fat oxidation. We show that 1 h of acute exercise increases the length of contact between LDs and mitochondria, irrespective of obesity or type 2 diabetes. This contact length between LDs and mitochondria is not associated with a net decrease in the LD volumetric density after the acute exercise. However, it correlates with the fat oxidation rate during exercise. Our data establish that exercise mediates contact between LDs and the mitochondrial network and that this effect is not impaired in individuals with type 2 diabetes or obesity.

Does Obesity Affect Neuromuscular and Cardiovascular Adaptations after a 3-Month Combined Exercise Program in Untrained Premenopausal Middle-Aged Women?

Previous studies indicated different acute adaptations between obese and lean individuals, while there is limited information with conflicting results regarding long-term adaptations. The aim of this study was to compare the efficacy of a 3-month integrated combined training between obese and lean middle-aged untrained premenopausal women. In total, 72 women (36 obese/36 lean) were divided into four groups: (a) obese exercise (OB-EG), (b) obese control (OB-CG), (c) lean exercise (L-EG), and (d) lean control (L-CG). The exercise groups followed a 3-month (3 times/week) integrated combined aerobic and strength training program. Health indices (body composition, body circumferences, blood pressure, respiratory function), functional capacity (flexibility, balance), and physical fitness (strength, aerobic capacity) were measured before and after the 3-month time period. Participants' enjoyment was also assessed following the program. OB-EG and L-EG significantly improved (p < 0.05) similarly across all functional capacity and physical fitness indices (10-76%; depending on the evaluation index), except balance and strength indices of the non-preferred limb where OB-EG showed greater improvement (reducing the existing pre-training strength/balance asymmetries) than L-EG. Furthermore, both obese and lean individuals showed similarly high levels of enjoyment. This program could be effectively used in fitness settings causing similar neuromuscular and cardiovascular adaptations in obese and lean women.

Metabolomic Study of Aging in fa/fa Rats: Multiplatform Urine and Serum Analysis.

Zucker fatty (fa/fa) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young fa/fa rats up to 20 weeks of age, which can be considered early maturity in male fa/fa rats, the aim of our work was to extend the metabolomic characterization to significantly older animals. Therefore, the urinary profiles of obese fa/fa rats and their lean controls were monitored using untargeted NMR metabolomics between 12 and 40 weeks of age. At the end of the experiment, the rats were also characterized by NMR and LC-MS serum analysis, which was supplemented by a targeted LC-MS analysis of serum bile acids and neurotransmitters. The urine analysis showed that most of the characteristic differences detected in young obese fa/fa rats persisted throughout the experiment, primarily through a decrease in microbial co-metabolite levels, the upregulation of the citrate cycle, and changes in nicotinamide metabolism compared with the age-related controls. The serum of 40-week-old obese rats showed a reduction in several bile acid conjugates and an increase in serotonin. Our study demonstrated that the fa/fa model of genetic obesity is stable up to 40 weeks of age and is therefore suitable for long-term experiments.

AN EXPERIMENTAL INVESTIGATION OF THE MICROARCHITECTURE AND FRACTURE MECHANICS OF FEMURS OF ZUCKER DIABETIC FATTY (ZDF) RATS USING A SIDEWAYS FALL TEST

This study aims to assess the fracture mechanics of type-2 diabetic (T2D) femoral bone using innovative site-specific tests, whilst also examining the cortical and trabecular bone microarchitecture from various regions using micro-computed tomography (CT) of the femur as the disease progresses.Male [Zucker Diabetic Fatty (ZDF: fa/fa) (T2D) and Zucker Lean (ZL: fa/+) (Control)] rats were euthanized at 12-weeks of age, thereafter, right and left femora were dissected (Right femora: n = 6, per age, per condition; Left femora: n=8-9, per age, per condition). Right femurs were notched in the posterior of the midshaft. Micro-CT was used to scan the proximal femur, notched and unnotched femoral midshaft (cortical) of the right femur and the distal metaphysis (trabecular) of the left femur to investigate microarchitecture and composition. Right femurs were fracture toughness tested to measure the stress intensity factor (Kic) followed by a sideways fall test using a custom-made rig to investigate femoral neck mechanical properties.There was no difference in trabecular and cortical tissue material density (TMD) between T2D and control rats. Cortical thickness was unchanged, but trabeculae were thinner (p&lt;0.01) in T2D rats versus controls. However, T2D rats had a greater number of trabeculae (p&lt;0.05) although trabecular spacing was not different to controls. T2D rats had a higher connectivity distribution (p&lt;0.05) and degree of anisotropy (p&lt;0.05) in comparison to controls. There was no difference in the mechanical properties between strains.At 12-weeks of age, rats are experiencing early-stage T2Ds and the disease impact is currently not very clear. Structural and material properties are unchanged between strains, but the trabecular morphology shows that T2D rats have more trabecular struts present in order to account for the thinner trabeculae.

370 Epicardial adipose tissue and cardiometabolic health in youth-onset type 2 diabetes undergoing vertical sleeve gastrectomy

OBJECTIVES/GOALS: The goal of this study is to investigate the potential independent relationship between epicardial adipose tissue (EAT) and cardiometabolic health in youth-onset type 2 diabetes (T2D) and explore changes in EAT as a potential mediator of changes in cardiometabolic health in response to vertical sleeve gastrectomy (VSG). METHODS/STUDY POPULATION: We will assess glycemic control, insulin sensitivity and secretion in youth with T2D before and 3 months after VSG. Fasting labs, anthropometrics, and a 4-hour, frequently sampled liquid mixed meal tolerance test (45g carbohydrates, 14g fat, and 14g protein) were performed. Calculations included glucose, insulin, and GLP-1 area under the curve (AUC), Matsuda Index, HOMA-IR, and oral disposition index (DI). These cardiometabolic outcomes will then be assessed for associations between total EAT volume, measured from cardiac MRI. RESULTS/ANTICIPATED RESULTS: Previous studies have shown that individuals with obesity have higher EAT than lean controls, and adults with T2D have even higher EAT than obese controls. Therefore, we anticipate that our participants will have higher volume of EAT than what has been reported in the literature and that they will have worsening cardiometabolic outcomes without MBS. Our anticipated results will include: Weight and BMI, hemoglobin A1c, diabetes medications, Matsuda Index, HOMA-IR, DI, and glucose and insulin AUC during an MMTT. Cardiac MRI's are being analyzed and will give total EAT volume and will be analyzed for correlations with the cardiometabolic outcomes of body composition, aortic stiffness, blood pressure, cardiac structure and function, as well as lipid panel and insulin sensitivity. DISCUSSION/SIGNIFICANCE: This study is the first to specifically assess EAT in adolescents with T2D. The assessment of EAT will be done with gold-standard MRI and correlated with cardiometabolic health assessed by gold-standard methods. Together, the results will give insight into EAT as a potential independent cardiometabolic risk factor in adolescents undergoing VSG.

PYY (3-36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry

BackgroundProlonged high fat feeding negatively impacts pancreatic and intestinal morphology. In this regard, direct effects of PYY(3–36) on intestinal cell and pancreatic islet morphometry are yet to be fully explored in the setting of obesity. MethodsWe examined the influence of 21-days twice daily treatment with PYY(3–36) on these parameters in mice fed a high fat diet (HFD). ResultsPYY(3–36) treatment decreased food intake, body weight and circulating glucose in HFD mice. In terms of intestinal morphology, crypt depth was restored to control levels by PYY(3–36), with an additional enlargement of villi length. PYY(3–36) also reversed HFD-induced decreases of ileal PYY, and especially GLP-1, content. HFD increased numbers of PYY and GIP positive ileal cells, with PYY(3–36) fully reversing the effect on PYY cell detection. There were no obvious differences in the overall number of GLP-1 positive ileal cells in all mice, barring PYY(3–36) marginally decreasing GLP-1 villi cell immunoreactivity. Within pancreatic islets, PYY(3–36) significantly decreased alpha-cell area, whilst islet, beta-, PYY- and delta-cell areas remained unchanged. However, PYY(3–36) increased the percentage of beta-cells while also reducing percentage alpha-cell area. This was related to PYY(3-36)-induced reductions of beta-cell proliferation and apoptosis frequencies. Co-localisation of islet PYY with glucagon or somatostatin was elevated by PYY(3–36), with GLP-1/glucagon co-visualisation increased when compared to lean controls. ConclusionPYY(3–36) exerts protective effects on pancreatic and intestinal morphology in HFD mice linked to elevated ileal GLP-1 content. General significanceThese observations highlight mechanisms linked to the metabolic and weight reducing benefits of PYY(3–36).

Obese asthma phenotypes display distinct plasma biomarker profiles.

Obese asthma is a complex phenotype and further characterization of the pathophysiology is needed. This study aimed to explore inflammation-related plasma biomarkers in lean and overweight/obese asthmatics. We elucidated levels of inflammation-related plasma proteins in obese asthma phenotypes in the population-based cohort BAMSE (Swedish: Children, Allergy, Milieu, Stockholm, Epidemiology) using data from 2069 24-26-year-olds. Subjects were divided into lean asthma (n=166), lean controls (n=1440), overweight/obese asthma (n=73) and overweight/obese controls (n=390). Protein levels (n=92) were analysed using the Olink Proseek Multiplex Inflammation panel. Of the 92 included proteins, 41 were associated with lean and/or overweight/obese asthma. The majority of proteins associated with overweight/obese asthma also associated with overweight/obesity among non-asthmatics. Beta-nerve growth factor (BetaNGF), interleukin 10 (IL-10), and matrix metalloproteinase 10 (MMP10) were associated only with lean asthma while C-C motif chemokine 20 (CCL20), fibroblast growth factor 19 (FGF19), interleukin 5 (IL-5), leukemia inhibitory factor (LIF), tumor necrosis factor ligand superfamily member 9 (TNFRSF9), and urokinase-type plasminogen activator (uPA) were associated only with overweight/obese asthma. Overweight/obesity modified the association between asthma and 3 of the proteins: fibroblast growth factor 21 (FGF21), interleukin 4 (IL-4), and urokinase-type plasminogen activator (uPA). In the overweight/obese group, interleukin-6 (IL-6) was associated with non-allergic asthma but not allergic asthma. These data indicate distinct plasma protein phenotypes in lean and overweight/obese asthmatics which, in turn, can impact upon therapeutic approaches.

Study on the mechanism of a lean construction safety planning and control system: An empirical analysis in China

Despite the fact that lean construction (LC) has been shown to improve construction safety, little research has been conducted to investigate how LC technologies could be applied to safety management. This study aimed to close the gap by developing a safety planning and control (SPC) process based on LC technologies and evaluating it using structural equation modeling. The process was based on the last planner system (LPS) research framework and consisted of four sub-systems (i.e., the analysis layer, the planning layer, the control layer, and the performance layer). Data was gathered from 300 Chinese construction projects. The findings will serve as a guide for construction stakeholders looking to improve the efficiency of safety management by incorporating some LC technologies into the SPC process. And the four sub-systems work together to create a positive circulation system that aids in the long-term improvement of construction safety management.

Circulating irisin in nonalcoholic fatty liver disease: an updated meta-analysis.

Exogenous administration of recombinant irisin may reverse hepatic steatosis and steatohepatitis. However, it remains controversial as to whether nonalcoholic fatty liver disease (NAFLD) shows reduced circulating (serum/plasma) irisin levels. A meta-analysis was conducted to address this issue. A literature search of databases was performed up to June 2021. Observational studies that reported circulating irisin in NAFLD ascertained by any methods (e.g. ultrasonography or magnetic resonance) and compared with any controls were eligible for inclusion. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were obtained using a random-effects meta-analysis model. Eleven studies enrolling 1277 NAFLD cases and 944 non-NAFLD controls were included. The approaches used for NAFLD ascertainment included ultrasonography (4 studies), magnetic resonance (3 studies), and liver biopsy (5 studies). Meta-analysis showed that circulating irisin in NAFLD was comparable to any non-NAFLD controls (10 studies with 11 datasets; SMD -0.09, 95% CI: -0.48 to 0.29), including the body mass index (BMI)-matched and lean controls (both p ≥ 0.80). Restricting studies to NAFLD ascertained by magnetic resonance or liver biopsy rather than ultrasonography showed that serum irisin was reduced in NAFLD (5 studies, SMD -0.63, 95% CI: -1.14 to -0.13). Meta-analysis also suggested that circulating irisin did not differ between mild and moderate-to-severe NAFLD (7 studies; SMD 0.02, 95% CI: -0.25 to 0.30), and this association was not significantly moderated by study location (Europe versus Asia). Circulating irisin in NAFLD did not differ from any non-NAFLD controls and was unlikely to be affected by disease severity or racial-ethnic difference.

Kctd17-mediated Chop degradation promotes adipogenic differentiation

Obesity is commonly associated with excessive adipogenesis, a process by which preadipocytes undergo differentiation into mature adipocytes; however, the mechanisms underlying adipogenesis are not completely understood. Potassium channel tetramerization domain-containing 17 (Kctd17) belongs to the Kctd superfamily and act as a substrate adaptor of the Cullin 3-RING E3 ubiquitin ligase, which is involved in a wide variety of cell functions. However, its function in the adipose tissue remains largely unknown. Here, we found that Kctd17 expression levels were increased in white adipose tissue, especially in adipocytes, in obese mice compared to lean control mice. Gain or loss of function of Kctd17 in preadipocytes inhibited or promoted adipogenesis, respectively. Furthermore, we found that Kctd17 bound to C/EBP homologous protein (Chop) to target it for ubiquitin-mediated degradation, and this process was likely associated with increased adipogenesis. In conclusion, these data suggest that Kctd17 plays an important role in adipogenesis and can be a novel therapeutic target for obesity.

Impaired Organokine Regulation in Non-Diabetic Obese Subjects: Halfway to the Cardiometabolic Danger Zone

Altered organokine expression contributes to increased cardiometabolic risk in obesity. Our aim was to evaluate the associations of serum afamin with glucose homeostasis, atherogenic dyslipidemia, and other adipokines in severe obesity to clarify the early metabolic alterations. 106 non-diabetic obese (NDO) subjects and 62 obese patients with type 2 diabetes matched for age, gender, and body mass index (BMI) were enrolled in this study. We compared their data with 49 healthy, lean controls. Serum afamin and retinol-binding protein 4 (RBP4), as well as plasma plasminogen activator inhibitor-1 (PAI-1), were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint gel electrophoresis. Afamin and PAI-1 found to be significantly higher in the NDO and T2M group (p < 0.001 and p < 0.001, respectively) than in the controls. In contrast, RBP4 was unexpectedly lower in the NDO and T2DM group compared to controls (p < 0.001). Afamin showed negative correlations with mean LDL size and RBP4, but positive correlations with anthropometric, glucose/lipid parameters, and PAI-1 in both the overall patients and the in NDO + T2DM groups. BMI, glucose, intermediate HDL, and small HDL were predictors of afamin. Afamin may serve as a biomarker for the severity of cardiometabolic disturbances in obesity. The complexity of organokine patterns in NDO subjects draws attention to the diverse spectrum of obesity-related comorbidities.

Adiponectin–leptin ratio for the early detection of lean non-alcoholic fatty liver disease independent of insulin resistance

Background Lean Non-alcoholic Fatty Liver Disease (NAFLD) shares a similar disease burden to those of their overweight counterparts and should be detected early. We hypothesized that the adiponectin–leptin ratio (AL ratio) could be a good marker for early detection of lean NAFLD independent of insulin resistance. Materials and methods A total of 575 adults without diabetes were enrolled in a community-based study. The subjects were stratified into the lean controls, lean NAFLD, simple overweight/obesity and overweight/obesity NAFLD groups according to body mass index (BMI) and ultrasonographic fatty liver indicators. Serum adiponectin and leptin levels were measured by enzyme-linked immunosorbent assay. Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD in relation to the tertiles of serum AL concentration after adjustment. Receiver operating characteristic (ROC) analyses were applied to evaluate the diagnostic performance of the AL ratio for NAFLD. Results The mean age of the participants was 42.8 ± 11.5 years. Comparing with the lean controls, the odds of having lean NAFLD for the highest versus the lowest tertile of AL ratio was 0.28(95%CI: 0.12–0.69) after adjustment. Putting AL ratio, BMI, triglyceride, AST/ALT ratio to the diagnosis performance of NAFLD, the ROC was 0.85 (95% CI: 0.82–0.88), 0.83 (95% CI 0.78–0.87) and 0.86 (95% CI 081–0.91) for all NAFLD, NAFLD in women and NAFLD in men, respectively. (p < .001). Conclusions The study revealed that the AL ratio could be a good biomarker to early distinguish lean NAFLD patients from lean controls independent of insulin resistance. [AQ3] Key messages The prevalence of non-alcoholic fatty liver disease (NAFLD) increases globally and is related to liver diseases and metabolic dysfunctions. Lean subset of NAFLD shares a similar disease burden to those of their overweight counterparts and should be detected early. Adiponectin–leptin ratio were associated with the severity of steatosis and was a predictor of obese NAFLD better than each single adipokine. To date, there is no investigation that explores specifically for the relationship between lean NAFLD and AL ratio. Our study found that adiponectin–leptin ratio is a sole independent marker regardless of insulin resistance in lean NAFLD. Having lean NAFLD for the highest versus the lowest tertile of adiponectin–leptin ratio was 0.28(95%CI: 0.12–0.69) after adjustment of age, sex, current smoking, exercise habits, HOMA-IR and AST/ALT. ROC for the NAFLD performance is good for the early detection (0.85; 95% CI: 0.82–0.88). Further rigorous investigation is necessary and should be promptly performed.