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We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD). Endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the ‘unhealthy’ adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates metabolically adverse effects and effectively reverses metabolic dysfunction induced during HFD exposure. Collectively, our findings demonstrate that endotrophin exerts a major influence in adipose tissue, eventually resulting in systemic elevation of pro-inflammatory cytokines and insulin resistance, and the results establish endotrophin as a potential target in the context of metabolism and cancer.

Aims Despite increased recognition as a chronic disease, obesity remains greatly underdiagnosed and undertreated. We aimed to identify international perceptions, attitudes, behaviours and barriers to effective obesity care in people with obesity (PwO) and healthcare professionals (HCPs). Materials and methods An online survey was conducted in 11 countries. Participants were adults with obesity and HCPs who were primarily concerned with direct patient care. Results A total of 14 502 PwO and 2785 HCPs completed the survey. Most PwO (68%) and HCPs (88%) agreed that obesity is a disease. However, 81% of PwO assumed complete responsibility for their own weight loss and only 44% of HCPs agreed that genetics were a barrier. There was a median of three (mean, six) years between the time PwO began struggling with excess weight or obesity and when they first discussed their weight with an HCP. Many PwO were concerned about the impact of excess weight on health (46%) and were motivated to lose weight (48%). Most PwO (68%) would like their HCP to initiate a conversation about weight and only 3% were offended by such a conversation. Among HCPs, belief that patients have little interest in or motivation for weight management may constitute a barrier for weight management conversations. When discussed, HCPs typically recommended lifestyle changes; however, more referrals and follow‐up appointments are required. Conclusions Our international dataset reveals a need to increase understanding of obesity and improve education concerning its physiological basis and clinical management. Realization that PwO are motivated to lose weight offers an opportunity for HCPs to initiate earlier weight management conversations.

A diet-induced negative energy balance triggers compensatory mechanisms, e.g., lower metabolic rate and increased appetite. However, knowledge about potential compensatory mechanisms triggered by increased aerobic exercise is limited. A randomized controlled trial was performed in healthy, sedentary, moderately overweight young men to examine the effects of increasing doses of aerobic exercise on body composition, accumulated energy balance, and the degree of compensation. Eighteen participants were randomized to a continuous sedentary control group, 21 to a moderate-exercise (MOD; 300 kcal/day), and 22 to a high-exercise (HIGH; 600 kcal/day) group for 13 wk, corresponding to ϳ30 and 60 min of daily aerobic exercise, respectively. Body weight (MOD: Ϫ3.6 kg, P Ͻ 0.001; HIGH: Ϫ2.7 kg, P ϭ 0.01) and fat mass (MOD: Ϫ4.0 kg, P Ͻ 0.001 and HIGH: Ϫ3.8 kg, P Ͻ 0.001) decreased similarly in both exercise groups. Although the exercise-induced energy expenditure in HIGH was twice that of MOD, the resulting accumulated energy balance, calculated from changes in body composition, was not different (MOD: Ϫ39.6 Mcal, HIGH: Ϫ34.3 Mcal, not significant). Energy balance was 83% more negative than expected in MOD, while it was 20% less negative than expected in HIGH. No statistically significant changes were found in energy intake or nonexercise physical activity that could explain the different compensatory responses associated with 30 vs. 60 min of daily aerobic exercise. In conclusion, a similar body fat loss was obtained regardless of exercise dose. A moderate dose of exercise induced a markedly greater than expected negative energy balance, while a higher dose induced a small but quantifiable degree of compensation.exercise; body weight regulation; compensatory mechanisms; energy balance ALTHOUGH A MODERN SEDENTARY lifestyle along with overeating has been put forward as "Big Two" factors in the etiology of obesity (3,10,29), the outcomes of structured exercise programs designed to promote weight loss are often modest (42,58). This has led to the general (mis)conception that exercise, in itself, is a poor weight management strategy (20,42,49). Apart from a potential lack of compliance, the discrepancy between predicted and observed weight loss is likely due to a combination of physiological and behavioral compensatory changes affecting energy balance. These compensatory changes cause the accumulated energy balance during an exercise intervention to be less negative than would be theoretically predicted from the exercise-induced energy expenditure (ExEE), i.e., the total amount of energy expenditure that is caused by the exercise intervention (12,32,34).Body energy stores are protected against long-term negative energy balance resulting from caloric restriction by a greater than predicted reduction in resting energy expenditure (REE) (28), a decrease in nonexercise activity thermogenesis (NEAT) (40,45), an increase in the metabolic efficiency of physical activity (16,35), and an increase in hedonic (21) and hormonal mediators o...

Objective Previous studies have shown additive weight loss when intensive behavioral therapy (IBT) was combined with weight‐loss medication. The present multisite study provides the first evaluation, in primary care, of the effect of the Centers for Medicare and Medicaid Services–based IBT benefit, delivered alone (with placebo) or in combination with liraglutide 3.0 mg. Methods The Satiety and Clinical Adiposity—Liraglutide Evidence in individuals with and without diabetes (SCALE) IBT was a 56‐week, randomized, double‐blind, placebo‐controlled, multicenter trial in individuals with obesity who received liraglutide 3.0 mg (n = 142) or placebo (n = 140) as an adjunct to IBT. Results At week 56, mean weight loss with liraglutide 3.0 mg plus IBT was 7.5% and 4.0% with placebo combined with IBT (estimated treatment difference [95% CI]–3.4% [–5.3% to –1.6%], P = 0.0003). Significantly more individuals on liraglutide 3.0 mg than placebo achieved ≥ 5% weight loss (61.5% vs. 38.8%; odds ratio [OR] 2.5% [1.5% to 4.1%], P = 0.0003), > 10% weight loss (30.5% vs. 19.8%; OR 1.8% [1.0% to 3.1%], P = 0.0469), and > 15% weight loss (18.1% vs. 8.9%; OR 2.3% [1.1% to 4.7%], P = 0.0311). Liraglutide 3.0 mg in combination with IBT was well tolerated, with no new safety signals identified. Conclusions In a primary care setting, Centers for Medicare and Medicaid Services–based IBT produced clinically meaningful weight loss at 56 weeks, enhanced by the addition of liraglutide 3.0 mg.

(7), but in contrast to these previous studies, apart from including younger and only moderately overweight men, our exercise training program included bouts of high intensity exercise. We hypothesized that endurance training, also without a concomitant weight loss, would increase metabolic health. Methods and Procedures ParticipantsVolunteers were recruited through advertising in newspapers and on the internet. Inclusion criteria were male sex, age 20-40 years, BMI 25-30 kg/m 2

Obese individuals are characterized by low circulating adiponectin concentrations and an increased number of macrophages in adipose tissue, which is believed to be causally associated with chronic low-grade inflammation and insulin resistance. Regular physical exercise decreases overall morbidity in obese subjects, which may be due to modulations of inflammatory pathways. In this randomized clinical trial we investigated the separate effects of endurance training-induced weight loss, diet-induced weight loss, and endurance training per se (without weight loss) on plasma adiponectin multimer composition (Western blotting) and adipose tissue macrophage content (immunohistochemistry) in young, moderately overweight men. Weight loss and endurance training per se decreased whole body fat percentage in an additive manner. No intervention-induced changes were observed for plasma total adiponectin. Surprisingly, endurance training, irrespectively of any associated weight loss, shifted the adiponectin multimer distribution toward a lower molecular weight (21% decrease in HMW/LMW, P = 0.015), whereas diet-induced weight loss shifted the distribution toward a higher molecular weight (42% increase in HMW/MMW, P < 0.001). Furthermore, endurance training per se increased the number of anti-inflammatory CD163⁺ macrophages [from 12.7 ± 2.1 (means ± SE) to 16.1 ± 3.1 CD163⁺ cells/100 adipocytes, P = 0.013], whereas diet-induced weight loss tended to decrease CD68⁺ macrophages in subcutaneous abdominal adipose tissue. Thus regular physical exercise influences systemic and adipose tissue inflammatory pathways differently than diet-induced weight loss in younger, moderately overweight men. Our data suggest that some of the health benefits of a physically active lifestyle may occur through modulations of anti- rather than pro-inflammatory pathways in young, overweight men.

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