Body weight management is currently of major concern as the obesity epidemic is still a worldwide challenge. As women face more difficulties to lose weight than men, there is an urgent need to better understand the under...Body weight management is currently of major concern as the obesity epidemic is still a worldwide challenge. As women face more difficulties to lose weight than men, there is an urgent need to better understand the underlying reasons and mechanisms. Recent data have suggested that the use of oral contraceptive (OC) could be involved. The necessity of utilization and development of contraceptive strategies for birth regulation is undeniable and contraceptive pills appear as a quite easy approach. Moreover, OC also represent a strategy for the management of premenstrual symptoms, acne or bulimia nervosa. The exact impact of OC on body weight remains not clearly established. Thus, after exploring the potential underlying mechanisms by which OC could influence the two side of energy balance, we then provide an overview of the available evidence regarding the effects of OC on energy balance (i.e. energy expenditure and energy intake). Finally, we highlight the necessity for future research to clarify the cellular effects of OC and how the individualization of OC prescriptions can improve long-term weight loss management.
Bulló M, Papandreou C, García-Gavilán J
… +18 more, Ruiz-Canela M, Li J, Guasch-Ferré M, Toledo E, Clish C, Corella D, Estruch R, Ros E, Fitó M, Lee CH, Pierce K, Razquin C, Arós F, Serra-Majem L, Liang L, Martínez-González MA, Hu FB, Salas-Salvadó J
BACKGROUND: Tricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remai...BACKGROUND: Tricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF. METHODS: We used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d/l-2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use. RESULTS: Comparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d/l-2-hydroxyglutarate were associated with a higher risk of AF [OR (95% CI): 1.80 (1.21-2.67), 2.13 (1.45-3.13), 1.87 (1.25-2.81) and 1.95 (1.31-2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01-1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d/l-2-hydroxyglutarate were 2.15 (1.29-3.56), 2.16 (1.25-3.72), 2.63 (1.56-4.44) and 1.82 (1.10-3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF. CONCLUSION: These findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes.
BACKGROUND AND AIMS: The global prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. Chemokines and their receptors have potential as therapeutic targets of NAFLD. We investigated the role of CC chemokin...BACKGROUND AND AIMS: The global prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. Chemokines and their receptors have potential as therapeutic targets of NAFLD. We investigated the role of CC chemokine ligand 3 (CCL3) in the development of murine and human NAFLD. METHODS: CCL3-knockout mice (CCL3) and littermate CCL3 wild-type control mice (WT) were fed a high-cholesterol and high-fat (CL) diet for 16 weeks to induce NAFLD. We investigated the impact of CCL3 gene deletion in bone marrow cells and leptin-deficient ob/ob mice on CL diet-induced steatohepatitis. We assayed the serum CCL3 levels in 36 patients with biopsy-proven NAFLD and nine healthy control subjects. RESULTS: Compared with normal chow (NC), the CL diet induced steatohepatitis and hepatic fibrosis and elevated the plasma CCL3 level. In the liver, CCL3 protein colocalized with F4/80 macrophages, especially CD11c M1-like macrophages, rather than other cell types. CCL3 attenuated CL diet-induced steatohepatitis and fibrosis associated with M2-dominant liver macrophages compared with the WT. The reconstitution of bone marrow (BM) cells from CCL3 attenuated steatohepatitis in WT mice fed a CL diet. Furthermore, crossing CCL3 onto the ob/ob background prevented CL diet-induced NAFLD in ob/ob mice, which was associated with a lesser inflammatory phenotype of liver macrophages. Also, the serum and hepatic levels of CCL3 were significantly increased in patients with non-alcoholic steatohepatitis (NASH) compared to those with simple fatty liver (NAFL) and healthy subjects. CONCLUSION: Our data indicate that CCL3 facilitates macrophage infiltration into the liver and M1 polarization in the progression of steatohepatitis and highlight the need for further studies to determine the effect of CCL3-CCR1 and -CCR5 signaling blockade on the treatment of NAFLD.
BACKGROUND: The protective role of mildly elevated bilirubin against CVD and diabetes mellitus type 2 (DMT2) is associated with a favorable lipid phenotype. As the mechanistic understanding of this protection in humans r...BACKGROUND: The protective role of mildly elevated bilirubin against CVD and diabetes mellitus type 2 (DMT2) is associated with a favorable lipid phenotype. As the mechanistic understanding of this protection in humans remains elusive, we aimed to assess the metabolomics profile of mildly hyperbilirubinemic (Gilbert's syndrome; GS) individuals especially targeting lipid catabolism. METHODS AND RESULTS: Using NMR serum metabolomics of 56 GS individuals and 56 age and gender-matched healthy controls, GS individuals demonstrated significantly greater concentrations of acetylcarnitine (+20%, p < 0.001) and the ketone bodies, 3-hydroxybutyric acid (+132%, p < 0.001), acetoacetic acid (+95%, p < 0.001) and acetone (+46%, p < 0.001). Metabolites associated with an increased mitochondrial lipid metabolism such as citrate (+15%, p < 0.001), anaplerotic amino acid intermediates and creatinine were significantly greater and creatine significantly reduced in GS individuals. Stimulators of lipid catabolism including AMPK (+59%, p < 0.001), pPPARα (+24%, p < 0.001) and T3 (+9%, p = 0.009) supported the metabolomics data while concomitantly blood glucose and insulin (-33%, p = 0.002) levels were significantly reduced. We further showed that the increased lipid catabolism partially mediates the favorable lipid phenotype (lower triglycerides) of GS individuals. Increased trimethylamine (+35%, p < 0.001) indicated changes in trimethylamine metabolism, an emerging predictor of metabolic health. CONCLUSION: We showed an enhanced lipid catabolism in mildly hyperbilirubinemic individuals, novel evidence as to why these individuals are leaner and protected against chronic metabolic diseases emphasizing bilirubin to be a promising future target in obese and dyslipidemia patients.
BACKGROUND: Duodenal mucosal resurfacing (DMR) is a novel day-case endoscopic intervention which results in weight loss-independent reductions in HbA1c in patient with type 2 diabetes mellitus (T2DM). We hypothesized tha...BACKGROUND: Duodenal mucosal resurfacing (DMR) is a novel day-case endoscopic intervention which results in weight loss-independent reductions in HbA1c in patient with type 2 diabetes mellitus (T2DM). We hypothesized that DMR works by increasing insulin sensitivity and we aimed to investigate the mechanism of action of DMR through longitudinal metabolic phenotyping in humans. METHODS: Thirty-two insulin-resistant women with polycystic ovary syndrome (PCOS) and obesity were randomised in a double-blinded manner to DMR or sham endoscopy. They underwent measurements of insulin sensitivity using euglycaemic hyperinsulinaemic clamps, insulin secretion using oral glucose tolerance tests and reproductive function using weekly reproductive hormone profiles and ovarian ultrasonography for 6 months post-intervention. RESULTS: A small increase in total body insulin sensitivity measured by the clamp was observed in both groups at week 12. An increase in insulin sensitivity, as measured by HOMA-IR, was observed in both groups at week 24. There was an increase in the number of menses (median 2 DMR, 0.5 sham). There were no significant differences between the two groups in these outcomes or insulin secretion. CONCLUSIONS: These findings suggest that DMR does not work by increasing insulin sensitivity in euglycaemic, insulin resistant women with PCOS. The procedure may exert its effects only in the context of hyperglycaemia or pathologically hyperplastic, insulin-desensitised duodenal mucosa.
BACKGROUND/OBJECTIVES: We evaluated the role of the presence of non-alcoholic fatty liver disease (NAFLD) at baseline in the transition from metabolically healthy to metabolically unhealthy obesity (MHO to MUO) ten years...BACKGROUND/OBJECTIVES: We evaluated the role of the presence of non-alcoholic fatty liver disease (NAFLD) at baseline in the transition from metabolically healthy to metabolically unhealthy obesity (MHO to MUO) ten years later. METHODS: A prospective cohort study (ATTICA study, Greece) was performed between 2002 and 2012 studying a sample from the greater metropolitan Athens area. In total, 1514 (49·8%) men and 1528 (50.2%) women (aged >18 years old) free-of-CVD were included. Healthy metabolic status was defined as absence of all NCEP ATP III (2005) metabolic syndrome components. NAFLD was defined according to validated liver steatosis indices. Follow-up CVD assessment (2011-2012) was achieved in n = 2020 participants (n = 317 cases). RESULTS: NAFLD prevalence among MHO participants ranged from 29% to 39% according to the specific NAFLD score used. MHO participants who developed metabolically unhealthy status had about two times higher odds to have NAFLD at baseline compared with their metabolically healthy normal weight counterparts whereas stable MHO was not associated significantly with NAFLD. Moreover, MHO status accompanied by NAFLD was associated with increased CVD risk (Hazard Ratio = 2.90 95% Confidence Interval (1.35, 5.40)) in comparison to their non-NAFLD MHO counterparts. Further analysis revealed that in the obese, NAFLD indices and not simply visceral adiposity increased significantly the ability of metabolic status (using standard definition) to predict long-term CVD incidence. CONCLUSIONS: Considering NAFLD, even when assessed using validated indices only, in the clinical assessment of apparently healthy obese individuals predicts who is to develop MUO and contributes independently and more accurately to defining future cardiometabolic risk.
Neurons obtain glucose from extracellular environment for energy production mainly depending on glucose transporter 3 (GLUT3). GLUT3 uptakes glucose with high affinity and great transport capacity, and is important for n...Neurons obtain glucose from extracellular environment for energy production mainly depending on glucose transporter 3 (GLUT3). GLUT3 uptakes glucose with high affinity and great transport capacity, and is important for neuronal energy metabolism. This review summarized the role of neuronal GLUT3 in brain metabolism, function and development under both physiological conditions and in diseases, aiming to provide insights into neuronal glucose metabolism and its effect on brain. GLUT3 stabilizes neuronal glucose uptake and utilization, influences brain development and function, and ameliorates aging-related manifestations. Neuronal GLUT3 is regulated by synaptic activity, hormones, nutrition, insulin and insulin-like growth factor 1 in physiological conditions, and is also upregulated by hypoxia-ischemia. GLUT3-related neuronal glucose and energy metabolism is possibly involved in the pathogenesis, pathophysiological mechanism, progression or prognosis of brain diseases, including Alzheimer's disease, Huntington's disease, attention-deficit/hyperactivity disorder and epilepsy. GLUT3 may be a promising therapeutic target of these diseases. This review also briefly discussed the role of other glucose transporters in neuronal glucose metabolism, which work together with GLUT3 to sustain and stabilize glucose and energy supply for neurons. Deficiency in these glucose transporters may also participate in brain diseases, especially GLUT1 and GLUT4.
Diabetic neuropathy is a neurodegenerative disorder that may alter both the somatic and autonomic peripheral nervous systems in the context of diabetes mellitus (DM). It is a prevalent and burdensome chronic complication...Diabetic neuropathy is a neurodegenerative disorder that may alter both the somatic and autonomic peripheral nervous systems in the context of diabetes mellitus (DM). It is a prevalent and burdensome chronic complication of DM, that requires timely management. Optimized glycemic control (mainly for type 1 DM), multifactorial intervention (mainly for type 2 DM), with lifestyle intervention/physical exercise, and weight loss represent the basis of management for diabetic distal symmetrical polyneuropathy, and should be implemented early in the disease course. Despite better understanding of the pathogenetic mechanisms of diabetic peripheral neuropathy, there is still a stringent need for more pathogenetic-based agents that would significantly modify the natural history of the disease. The paper reviews the available drugs and current recommendations for the management of distal symmetrical polyneuropathy, including pain management, and for diabetic autonomic neuropathy. Evaluation of drug combinations that would perhaps be more efficient in slowing the progression of the disease or even reversing it, and that would provide a better pain management is still needed.
AIM: The association of carbohydrate intake with diabetes risk remains uncertain. We aimed to evaluate the prospective associations of the amount and types of carbohydrate intake with new-onset diabetes. METHODS: A total...AIM: The association of carbohydrate intake with diabetes risk remains uncertain. We aimed to evaluate the prospective associations of the amount and types of carbohydrate intake with new-onset diabetes. METHODS: A total of 16,260 non-diabetic participants from the China Health and Nutrition Survey (CHNS) were included. Dietary intake was collected by three consecutive 24-h dietary recalls combined with a household food inventory. Participants with self-reported physician diagnosed diabetes, or fasting plasma glucose ≥7.0 mmol/L or glycated hemoglobin ≥6.5% during the follow-up were defined having new-onset diabetes. RESULTS: During a median follow-up of 9 years (158,930 person-years), 1100 participants developed diabetes. Overall, there was a U-shaped association between percent of energy from carbohydrate intake and new-onset diabetes, with minimal risk at 49-56% of energy from total carbohydrate intake (quartile 2) (P for nonlinearity <0.001). Moreover, there was an L-shaped association between high-quality carbohydrate intake and new-onset diabetes (P for nonlinearity <0.001), and a J-shaped association of low-quality carbohydrate intake with new-onset diabetes (P for nonlinearity <0.001). Furthermore, there was an inverse association between the plant-based low-carbohydrate diet scores for low-quality carbohydrate and new-onset diabetes. However, a reversed J-shaped association was found between the animal-based low-carbohydrate diet scores for low-quality carbohydrate and new-onset diabetes (P for nonlinearity <0.001). CONCLUSIONS: There was a U-shape association between percent of total carbohydrate intake and new-onset diabetes, with the lowest risk at 49-56% carbohydrate intake. Our findings provide some evidence for the intake of high-quality carbohydrate, and the substitution of plant-based products for low-quality carbohydrate for primary prevention of diabetes.
BACKGROUND/OBJECTIVES: Acyl-coenzyme A:cholesterol acyltransferases (ACATs) catalyze the formation of cholesteryl ester (CE) from free cholesterol to regulate intracellular cholesterol homeostasis. Despite the well-docum...BACKGROUND/OBJECTIVES: Acyl-coenzyme A:cholesterol acyltransferases (ACATs) catalyze the formation of cholesteryl ester (CE) from free cholesterol to regulate intracellular cholesterol homeostasis. Despite the well-documented role of ACATs in hypercholesterolemia and their emerging role in cancer and Alzheimer's disease, the role of ACATs in adipose lipid metabolism and obesity is poorly understood. Herein, we investigated the therapeutic potential of pharmacological inhibition of ACATs in obesity. METHODS: We administrated avasimibe, an ACAT inhibitor, or vehicle to high-fat diet-induced obese (DIO) mice via intraperitoneal injection and evaluated adiposity, food intake, energy expenditure, and glucose homeostasis. Moreover, we examined the effect of avasimibe on the expressions of the genes in adipogenesis, lipogenesis, inflammation and adipose pathology in adipose tissue by real-time PCR. We also performed a pair feeding study to determine the mechanism for body weight lowering effect of avasimibe. RESULTS: Avasimibe treatment markedly decreased body weight, body fat content and food intake with increased energy expenditure in DIO mice. Avasimibe treatment significantly lowered blood levels of glucose and insulin, and improved glucose tolerance in obese mice. The beneficial effects of avasimibe were associated with lower levels of adipocyte-specific genes in adipose tissue and the suppression of food intake. Using a pair-feeding study, we further demonstrated that avasimibe-promoted weight loss is attributed mainly to the reduction of food intake. CONCLUSIONS: These results indicate that avasimibe ameliorates obesity and its-related insulin resistance in DIO mice through, at least in part, suppression of food intake.
AIMS: Patients with diabetes have a higher incidence of infections with Candida albicans, Staphylococcus aureus and Mycobacterium tuberculosis, yet factors contributing to this increased risk are largely unknown. We hypo...AIMS: Patients with diabetes have a higher incidence of infections with Candida albicans, Staphylococcus aureus and Mycobacterium tuberculosis, yet factors contributing to this increased risk are largely unknown. We hypothesize that altered innate and adaptive immune responses during diabetes contribute to an increased susceptibility to infections. MATERIALS AND METHODS: We studied cytokine responses to ex vivo pathogenic stimulations in a cohort with type 1 diabetes (n = 243) and non-diabetic healthy control subjects (n = 56) using isolated peripheral blood mononuclear cells (PBMCs). Clinical phenotypical data including BMI, duration of diabetes, and HbA levels were collected and related to the cytokine production capacity. RESULTS: Adjusted for age, sex and BMI, the presence of diabetes was associated with significantly lower IL-1β, IL-6, TNF-α, and IL-17 production upon ex vivo stimulation of PBMCs with C. albicans and S. aureus (all, p < 0.05). In response to stimulation with M. tuberculosis only IL-17 (p < 0.001) was lower in patients with diabetes. Patients with the shortest diabetes duration had a significant lower IL-1β, IL-6 and TNF-α production (all, p < 0.01) after M. tuberculosis stimulation. Older patients had a significant lower IFN-γ (p < 0.05) production after stimulation with all three pathogens. HbA levels and BMI had no significant impact on cytokine production. CONCLUSIONS: PBMCs of patients with type 1 diabetes demonstrate significantly lower cytokine production in response to stimulation with several pathogens, which likely explain, at least in part, the increased susceptibility for these infections.
Laminins are extracellular matrix proteins that reside in the basement membrane and provide structural support in addition to promoting cellular adhesion and migration. Through interactions with cell surface receptors, l...Laminins are extracellular matrix proteins that reside in the basement membrane and provide structural support in addition to promoting cellular adhesion and migration. Through interactions with cell surface receptors, laminins stimulate intracellular signaling cascades which direct specific survival and differentiation outcomes. In metabolic tissues such as the pancreas, adipose, muscle, and liver, laminin isoforms are expressed in discrete temporal and spatial patterns suggesting that certain isoforms may support the development and function of particular metabolic cell types. This review focuses on the research to date detailing the expression of laminin isoforms, their potential function, as well as known pathways involved in laminin signaling in metabolic tissues. We will also discuss the current biomedical therapies involving laminins in these tissues in addition to prospective applications, with the goal being to encourage future investigation of laminins in the context of metabolic disease.
BACKGROUND: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in...BACKGROUND: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes. METHODS: We searched four databases until December 18th 2020, and trial registries until January 20th 2021. Two reviewers screened the studies, collected data, assessed the risk of bias, and graded the evidence for each outcome across studies, independently and in duplicate. Pre-specified outcomes of interest were mortality, ICU admission, invasive and non-invasive ventilation, hospitalization, time of hospital stay, disease severity and SARS-CoV-2 positivity. We only included data from peer-reviewed articles in our primary analyses. RESULTS: We identified 31 peer-reviewed observational studies. In our primary analysis, there was a positive trend between serum 25(OH)D level <20 ng/ml and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant. Mean 25(OH)D levels was 5.9 ng/ml (95% CI [-9.5, -2.3]) significantly lower in COVID-19 positive, compared to negative patients. The certainty of the evidence was very low. We identified 32 clinical trial protocols, but only three have published results to-date. The trials administer vitamin D doses of 357 to 60,000 IU/day, from one week to 12 months. Eight megatrials investigate the efficacy of vitamin D in outpatient populations. A pilot trial revealed a significant decrease in ICU admission with calcifediol, compared to placebo (OR = 0.003), but the certainty of the evidence was unclear. Another small trial showed that supplementation with cholecalciferol, 60,000 IU/day, decreased fibrinogen levels, but did not have an effect on D-dimer, procalcitonin and CRP levels, compared to placebo. The third trial did not find any effect of vitamin D supplementation on COVID-19 related health outcomes. CONCLUSION: While the available evidence to-date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant. Calcifediol supplementation may have a protective effect on COVID-19 related ICU admissions. The current use of high doses of vitamin D in COVID-19 patients is not based on solid evidence. It awaits results from ongoing trials to determine the efficacy, desirable doses, and safety, of vitamin D supplementation to prevent and treat COVID-19 related health outcomes.
BACKGROUND: Patients with type 2 diabetes (T2D) are at increased risk of both cardiovascular disease (CVD) and advanced liver fibrosis related to non-alcoholic fatty liver disease (NAFLD). Statin use is known to reduce t...BACKGROUND: Patients with type 2 diabetes (T2D) are at increased risk of both cardiovascular disease (CVD) and advanced liver fibrosis related to non-alcoholic fatty liver disease (NAFLD). Statin use is known to reduce the incidence of CVD while evidence on an effect on NAFLD severity is limited. METHODS: This is a cross-sectional study performed with data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey (NHANES). The target population consisted in adult patients with T2D and reliable vibration-controlled transient elastography (VCTE) results. Presence of liver fibrosis and steatosis were assessed by the median values of liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), respectively. Patients with evidence of viral hepatitis and significant alcohol consumption were excluded. Logistic regression analysis was performed to evaluate the association between statin treatment and both steatosis and advanced (≥F3) liver fibrosis after adjustment for potential confounders. RESULTS: The study population consisted in 744 patients (age: 61 ± 1 years, BMI: 33.3 ± 0.5 kg/m). NAFLD (CAP≥274 dB/m) was present in 74.9% of patients (95% CI 69.2-79.8) and 14.5% (95% CI 10.8-19.2) had advanced fibrosis (LSM ≥ 9.7 kPa). After adjustment for age, sex, race-ethnicity, BMI, albumin, total cholesterol, HbA1c, triglycerides and liver enzymes, statin use was associated with lower odds of advanced fibrosis (OR 0.35, 95% CI 0.13-0.90, p = 0.03). No significant interaction was found between statin use and steatosis. CONCLUSION: Given the absence of approved therapies for NAFLD-fibrosis, it would be reasonable to initiate specific randomized controlled trials with statins.
BACKGROUND & AIMS: Cholesterol gallstone disease (CGD) is a common gastrointestinal disease. Liraglutide, an analogue of glucagon-like peptide 1, has been approved to treat type 2 diabetes. Clinical studies have suggeste...BACKGROUND & AIMS: Cholesterol gallstone disease (CGD) is a common gastrointestinal disease. Liraglutide, an analogue of glucagon-like peptide 1, has been approved to treat type 2 diabetes. Clinical studies have suggested a potential role of liraglutide in CGD. METHODS: Mice were subcutaneously injected with liraglutide, then fed a lithogenic diet. Bile duct cannulation was performed to collect bile output in mice. Intestinal-specific ablation or pharmacological inhibition of farnesoid X receptor (FXR) was used to study its functions in CGD. RESULTS: Liraglutide could protect mice against CGD. Liraglutide treatment increased the biliary concentration of cholesterol, phospholipids and bile acids and thereby decreased the cholesterol saturation index. The resistance to CGD conferred by liraglutide is likely a result of increased bile acid synthesis and efficient bile acid transport. The expression of a key bile acid synthetic enzyme, Cyp7a1, was significantly increased in liraglutide-treated mice. The increased expression of Cyp7a1 resulted from a relieved suppression signal of Fgf15 from the ileum. Mechanistically, liraglutide treatment altered bile acid composition and suppressed FXR activity in the ileum. Genetic ablation or pharmacological inhibition of FXR in the intestine protected mice against CGD. More importantly, intestinal FXR was required for liraglutide-mediated regulation of hepatic expression of Cyp7a1. CONCLUSION: Liraglutide improved CGD by increasing bile acid secretion and decreasing cholesterol saturation index. Liraglutide attenuates the negative feedback inhibition of bile acids through inhibiting intestinal FXR activity. Our results suggest that liraglutide may represent a novel way for treating or preventing cholesterol gallstones in individuals with high risk of CGD.
BACKGROUND: Type 2 diabetes (T2DM) is an age-associated disease characterized by hyperglycemia due to insulin resistance and decreased beta-cell function. DNA damage accumulation has been associated with T2DM, but whethe...BACKGROUND: Type 2 diabetes (T2DM) is an age-associated disease characterized by hyperglycemia due to insulin resistance and decreased beta-cell function. DNA damage accumulation has been associated with T2DM, but whether DNA damage plays a role in the pathogenesis of the disease is unclear. Here, we used mice deficient for the DNA excision-repair gene Ercc1 to study the impact of persistent endogenous DNA damage accumulation on energy metabolism, glucose homeostasis and beta-cell function. METHODS: ERCC1-XPF is an endonuclease required for multiple DNA repair pathways and reduced expression of ERCC1-XPF causes accelerated accumulation of unrepaired endogenous DNA damage and accelerated aging in humans and mice. In this study, energy metabolism, glucose metabolism, beta-cell function and insulin sensitivity were studied in Ercc1 mice, which model a human progeroid syndrome. RESULTS: Ercc1 mice displayed suppression of the somatotropic axis and altered energy metabolism. Insulin sensitivity was increased, whereas, plasma insulin levels were decreased in Ercc1 mice. Fasting induced hypoglycemia in Ercc1 mice, which was the result of increased glucose disposal. Ercc1 mice exhibit a significantly reduced beta-cell area, even compared to control mice of similar weight. Glucose-stimulated insulin secretion in vivo was decreased in Ercc1 mice. Islets isolated from Ercc1 mice showed increased DNA damage markers, decreased glucose-stimulated insulin secretion and increased susceptibility to apoptosis. CONCLUSION: Spontaneous DNA damage accumulation triggers an adaptive response resulting in improved insulin sensitivity. Loss of DNA repair, however, does negatively impacts beta-cell survival and function in Ercc1 mice.
BACKGROUND: We recently demonstrated that thrifty subjects, characterized by a greater decrease in 24 h energy expenditure (24hEE) during short-term fasting, have less capacity for cold-induced thermogenesis (CIT) during...BACKGROUND: We recently demonstrated that thrifty subjects, characterized by a greater decrease in 24 h energy expenditure (24hEE) during short-term fasting, have less capacity for cold-induced thermogenesis (CIT) during 24 h of mild cold exposure. OBJECTIVE: As cold-induced brown adipose tissue activation (CIBA) is a determinant of CIT, we sought to investigate whether thrifty individuals also have reduced CIBA. METHODS: Twenty-four healthy subjects (age: 29.8 ± 9.5y, body fat: 27.3 ± 12.4%, 63% male) were admitted to our clinical research unit and underwent two 24hEE assessments in a whole-room indirect calorimeter during energy balance and fasting conditions at thermoneutrality to quantify their degree of thriftiness. Positron emission tomography/computed tomography scans were performed after exposure to 16 °C for 2 h to quantify peak CIBA. RESULTS: A greater decrease in 24hEE during fasting was associated with lower peak CIBA (r = 0.50, p = 0.01), such that a 100 kcal/day greater reduction in 24hEE related to an average 3.2 g/mL lower peak CIBA. CONCLUSION: Our results indicate that reduced CIBA is a metabolic trait of the thrifty phenotype which might explain reduced CIT capacity and greater predisposition towards weight gain in individuals with a thrifty metabolism.