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Background: Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity. Methods: ASGR1 deficient mice (ASGR1−/−) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration. Results: ASGR1−/− mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1−/− mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1−/− have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function. Conclusion: ASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage. [ABSTRACT FROM AUTHOR]

Background: Distinguishable sex differences exist in fat mass and muscle mass. High fat mass and low muscle mass are independently associated with cardiovascular disease (CVD) risk factors in people living with type 2 diabetes; however, it is unknown if the association between fat mass and CVD risk is modified by muscle mass, or vice versa. This study examined the sex-specific interplay between fat mass and muscle mass on CVD risk factors in adults with type 2 diabetes living with overweight and obesity. Methods: Dual-energy X-ray absorptiometry (DXA) measures were used to compute fat mass index (FMI) and appendicular muscle mass index (ASMI), and participants were separated into high-fat mass vs. low-fat mass and high-muscle mass vs. low-muscle mass. A two-way analysis of covariance (ANCOVA: high-FMI vs. low-FMI by high-ASMI vs. low-ASMI) was performed on CVD risk factors (i.e., hemoglobin A1C [A1C]; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; triglycerides; systolic and diastolic blood pressure; cardiorespiratory fitness, depression and health related-quality of life [HR-QoL]) at baseline and following a 1-year intensive lifestyle intervention (ILI) for females and males separately, with a primary focus on the fat mass by muscle mass interaction effects. Results: Data from 1,369 participants (62.7% females) who completed baseline DXA were analyzed. In females, there was a fat mass by muscle mass interaction effect on A1C (p = 0.016) at baseline. Post-hoc analysis showed that, in the low-FMI group, A1C was significantly higher in low-ASMI when compared to high-ASMI (60.3 ± 14.1 vs. 55.5 ± 13.5 mmol/mol, p = 0.023). In the high-FMI group, there was no difference between high-ASMI and low-ASMI (56.4 ± 12.5 vs. 56.5 ± 12.8 mmol/mol, p = 0.610). In males, only high-FMI was associated with higher A1C when compared to low-FMI (57.1 ± 14.4 vs. 54.2 ± 12.0 mmol/mol, p = 0.008) at baseline. Following ILI, there were significant fat mass by muscle mass interaction effects on changes in the mental component of HR-QoL in males. Conclusion: Considering that A1C predicts future CVD, strategies to lower A1C may be especially important in females with low fat and low muscle mass living with type 2 diabetes. Our results highlight the complicated and sex-specific contribution of fat mass and muscle mass to CVD risk factors. [ABSTRACT FROM AUTHOR]

Objective: Long-term treatment with up to 1.8 mg liraglutide improves cardiovascular and all-cause mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) and is currently under investigation in subjects without diabetes. Aim of our study was to investigate whether high dose (3 mg) short-term (5 weeks) treatment with liraglutide in obese patients with no overt type 2 diabetes affects metabolites, lipid and lipoprotein profile and components of activin–follistatin axis in cardiovascular beneficial or detrimental way. Research design and methods: Twenty obese patients participated in a randomized, placebo-controlled, cross-over, double-blind study and were administrated liraglutide 3 mg or placebo for 5 weeks. Metabolites, fatty acids, lipid–lipoprotein profile and concentrations of activins and follistatins (250 parameters) were assessed in serum at start and completion of each treatment. Results: Concentrations of important cardiovascular markers such as total, free and remnant cholesterol were reduced with liraglutide before and after adjusting for weight loss. Similarly, reductions in number of small and medium size LDL particles and in their total lipid concentration were observed with liraglutide and partially weight-loss related. Tyrosine levels were reduced and behenic acid levels were increased whereas only minor changes were observed in HDL, VLDL and IDL. Concentrations of activin AB and follistatin were significantly reduced in liraglutide-treated group. Conclusions: Treatment of obese patients without overt type 2 diabetes with high dose of liraglutide for a short period of time induces changes in lipid–lipoprotein and hormonal profile that are suggestive of lower risk of atherosclerosis and CVD. Trial registration ClinicalTrials.gov Identifier: NCT02944500. Study ID Number 2015P000327. Registered November 2016 [ABSTRACT FROM AUTHOR]

Background: Although hypercaloric interventions are associated with nutritional, endocrine, metabolic, and cardiovascular disorders in obesity experiments, a rational distinction between the effects of excess adiposity and the individual roles of dietary macronutrients in relation to these disturbances has not previously been studied. This investigation analyzed the correlation between ingested macronutrients (including sucrose and saturated and unsaturated fatty acids) plus body adiposity and metabolic, hormonal, and cardiovascular effects in rats with diet-induced obesity. Methods: Normotensive Wistar-Kyoto rats were submitted to Control (CD; 3.2 Kcal/g) and Hypercaloric (HD; 4.6 Kcal/g) diets for 20 weeks followed by nutritional evaluation involving body weight and adiposity measurement. Metabolic and hormonal parameters included glycemia, insulin, insulin resistance, and leptin. Cardiovascular analysis included systolic blood pressure profile, echocardiography, morphometric study of myocardial morphology, and myosin heavy chain (MHC) protein expression. Canonical correlation analysis was used to evaluate the relationships between dietary macronutrients plus adiposity and metabolic, hormonal, and cardiovascular parameters. Results: Although final group body weights did not differ, HD presented higher adiposity than CD. Diet induced hyperglycemia while insulin and leptin levels remained unchanged. In a cardiovascular context, systolic blood pressure increased with time only in HD. Additionally, in vivo echocardiography revealed cardiac hypertrophy and improved systolic performance in HD compared to CD; and while cardiomyocyte size was unchanged by diet, nuclear volume and collagen interstitial fraction both increased in HD. Also HD exhibited higher relative β-MHC content and β/α-MHC ratio than their Control counterparts. Importantly, body adiposity was weakly associated with cardiovascular effects, as saturated fatty acid intake was directly associated with most cardiac remodeling measurements while unsaturated lipid consumption was inversely correlated with these effects. Conclusion: Hypercaloric diet was associated with glycemic metabolism and systolic blood pressure disorders and cardiac remodeling. These effects directly and inversely correlated with saturated and unsaturated lipid consumption, respectively. [ABSTRACT FROM AUTHOR]