High-fat diet feeding reduces the expression of Rab3a, Rab3gap1, and Rab3Gap2 genes that are pivotal to neuronal exocytosis

The Rab3A and Rab3gaps are essential to the Ca+2-dependent neuronal exocytosis in the hypothalamus. The arcuate nucleus of the hypothalamus (ARC) controls food intake and energy expenditure. We have earlier described that the high-fat diet (HFD) feeding induces an obesity phenotype with high leptin production and alteration of proteins related to endosome sorting, and ubiquitination in the ARC of mice. In this study, real-time PCR data analysis revealed that HFD feeding decreases significantly Rab3a, Rab3gap1, and Rab3gap2 transcript levels in the ARC when compared to the group receiving a control diet. The decrease of Rab3gap1/2 transcript levels in the ARC was strongly associated with an increase in plasma leptin. Altogether, our studies demonstrate that HFD feeding could be altering the general network of endosome compartmentalization in the ARC of mice, contributing to a failure in exocytosis and receptor recycling.Graphical abstract

Dietary Restriction Induces a Stable Metabolic Obesity Phenotype in Drosophila Melanogaster

ObjectiveChallenges associated with current nutritional models to induce obesity in Drosophila melanogaster created a rationale for this study. The objective of the study was to investigate biochemical changes associated with high-fat diet (HFD), high sucrose diet (HSD), and a protein-restricted diet (DR) to induce a healthy metabolic obesity state. Drosophila melanogaster were fed to four experimental diets: regular food (control), HFD, HSD, and DR, for four weeks. Peristaltic waves were measured on 3rd instar larvae, while negative geotaxis, body mass, catalase activity; and total triglycerides, sterol, and protein were measured in adult Drosophila melanogaster.ResultsDR produced a Drosophila melanogaster phenotype which had superior adaptive advantages than that generated from HFD and HSD. HFD was the best phenotype during larval stages; however, locomotory, body mass, triglyceride, sterol concentrations, and catalase activity were highest in the DR phenotype during adulthood. High catalase activity and high triglyceride content demonstrated a balanced and healthy metabolic obesity status than in other phenotypes in the adult stage. Evolutionary changes are responsible for the selective advantage of the DR phenotype over the HFD phenotype. Prospective studies to guide therapy and community behavior should place more emphasis on the DR phenotypes in Drosophila melanogaster.

Impact of Morbid Obesity and Obesity Phenotype on Outcomes After Transcatheter Aortic Valve Replacement

Background There is a paucity of outcome data on patients who are morbidly obese (MO) undergoing transcatheter aortic valve replacement. We aimed to determine their periprocedural and midterm outcomes and investigate the impact of obesity phenotype. Methods and Results Consecutive patients who are MO (body mass index, ≥40 kg/m 2 , or ≥35 kg/m 2 with obesity‐related comorbidities; n=910) with severe aortic stenosis who underwent transcatheter aortic valve replacement in 18 tertiary hospitals were compared with a nonobese cohort (body mass index, 18.5–29.9 kg/m 2 , n=2264). Propensity‐score matching resulted in 770 pairs. Pre–transcatheter aortic valve replacement computed tomography scans were centrally analyzed to assess adipose tissue distribution; epicardial, abdominal visceral and subcutaneous fat. Major vascular complications were more common (6.6% versus 4.3%; P =0.043) and device success was less frequent (84.4% versus 88.1%; P =0.038) in the MO group. Freedom from all‐cause and cardiovascular mortality were similar at 2 years (79.4 versus 80.6%, P =0.731; and 88.7 versus 87.4%, P =0.699; MO and nonobese, respectively). Multivariable analysis identified baseline glomerular filtration rate and nontransfemoral access as independent predictors of 2‐year mortality in the MO group. An adverse MO phenotype with an abdominal visceral adipose tissue:subcutaneous adipose tissue ratio ≥1 (VAT:SAT) was associated with increased 2‐year all‐cause (hazard ratio [HR], 3.06; 95% CI, 1.20–7.77; P =0.019) and cardiovascular (hazard ratio, 4.11; 95% CI, 1.06–15.90; P =0.041) mortality, and readmissions (HR, 1.81; 95% CI, 1.07–3.07; P =0.027). After multivariable analysis, a (VAT:SAT) ratio ≥1 remained a strong predictor of 2‐year mortality (hazard ratio, 2.78; P =0.035). Conclusions Transcatheter aortic valve replacement in patients who are MO has similar short‐ and midterm outcomes to nonobese patients, despite higher major vascular complications and lower device success. An abdominal VAT:SAT ratio ≥1 identifies an obesity phenotype at higher risk of adverse clinical outcomes.

NBR1 is a critical step in the repression of thermogenesis of p62-deficient adipocytes through PPARγ

Activation of non-shivering thermogenesis is considered a promising approach to lower body weight in obesity. p62 deficiency in adipocytes reduces systemic energy expenditure but its role in sustaining mitochondrial function and thermogenesis remains unresolved. NBR1 shares a remarkable structural similarity with p62 and can interact with p62 through their respective PB1 domains. However, the physiological relevance of NBR1 in metabolism, as compared to that of p62, was not clear. Here we show that whole-body and adipocyte-specific ablation of NBR1 reverts the obesity phenotype induced by p62 deficiency by restoring global energy expenditure and thermogenesis in brown adipose tissue. Impaired adrenergic-induced browning of p62-deficient adipocytes is rescued by NBR1 inactivation, unveiling a negative role of NBR1 in thermogenesis under conditions of p62 loss. We demonstrate that upon p62 inactivation, NBR1 represses the activity of PPARγ, establishing an unexplored p62/NBR1-mediated paradigm in adipocyte thermogenesis that is critical for the control of obesity.

Association between different obesity phenotypes and hypothyroidism: a study based on a longitudinal health management cohort

Purpose Obese individuals have an increased risk of hypothyroidism. This study investigated the sex-specific association between obesity phenotypes and the development of hypothyroidism. Methods The study population was derived from a health management cohort in Shandong Provincial Hospital from 2012 to 2016. In total, 9011 baseline euthyroid adults were included and classified into four groups according to obesity phenotype: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUNO), and metabolically unhealthy obese (MUO). The median follow-up time was 1.92 (1.00–2.17) years. Incidence density was evaluated and a generalized estimation equation method was used to investigate the associations between obesity phenotypes and the development of hypothyroidism. Results The incidence densities of hypothyroidism in males with a consistent obesity phenotype were 12.19 (8.62–16.76), 15.87 (11.39–21.56), 14.52 (6.74–27.57), and 19.88 (14.06–27.34) per 1000 person-years in the MHNO, MHO, MUNO, and MUO groups, respectively. After adjusting for confounding factors, compared with the MHNO phenotype, the MHO, MUNO, and MUO phenotypes were independent risk factors for developing hypothyroidism in males. In the subgroup analysis, the MHO and MUO phenotypes were independent risk factors for developing hypothyroidism in males under 55 years, while the MUNO phenotype was an independent risk factor in males over 55 years. The MHO, MUNO, and MUO phenotypes were not independent risk factors for hypothyroidism in females. Conclusion Both obesity and metabolic abnormities are associated with a higher risk of hypothyroidism in males. The underlying mechanism of the sex and age differences in this association needs further investigation.