Dataset Information

Weight Cycling Increases Longevity Compared with Sustained Obesity in Mice.

ABSTRACT: OBJECTIVE:Despite the known health benefits of weight loss among persons with obesity, observational studies have reported that cycles of weight loss and regain, or weight cycling, are associated with increased mortality. To study whether weight loss must be sustained to achieve health and longevity benefits, we performed a randomized controlled feeding study of weight cycling in mice. METHODS:In early adult life, obese mice were randomized to ad libitum feeding to sustain obesity, calorie restriction to achieve a "normal" or intermediate body weight, or weight cycling (repeated episodes of calorie restriction and ad libitum refeeding). Body weight, body composition, and food intake were followed longitudinally until death. A subsample of mice was collected from each group for determination of adipose cell size, serum analytes, and gene expression. RESULTS:Weight loss significantly reduced adipose mass and adipocyte size in both sexes, whereas weight cycling animals regained body fat and cell size during refeeding. Sustained weight loss resulted in a dose-dependent decrease in mortality compared with ad libitum feeding. CONCLUSIONS:Weight cycling significantly increased life-span relative to remaining with obesity and had a similar benefit to sustained modest weight loss.

SUBMITTER: Smith DL

PROVIDER: S-EPMC6221135 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Weight Cycling Increases Longevity Compared with Sustained Obesity in Mice.

Smith Daniel L DL Yang Yongbin Y Nagy Tim R TR Patki Amit A Vasselli Joseph R JR Zhang Yiying Y Dickinson Stephanie L SL Allison David B DB

Obesity (Silver Spring, Md.) 20181101 11

<h4>Objective</h4>Despite the known health benefits of weight loss among persons with obesity, observational studies have reported that cycles of weight loss and regain, or weight cycling, are associated with increased mortality. To study whether weight loss must be sustained to achieve health and longevity benefits, we performed a randomized controlled feeding study of weight cycling in mice.<h4>Methods</h4>In early adult life, obese mice were randomized to ad libitum feeding to sustain obesity ...[more]

PMID: 30358151

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Project description:Obesity, a major health concern, results from an imbalance between energy intake and expenditure. Leptin-deficient ob/ob mice are paradigmatic of obesity, resulting from excess energy intake and storage. Mice lacking acyl-CoA oxidase 1 (Acox1), the first enzyme of the peroxisomal fatty acid β-oxidation system, are characterized by increased energy expenditure and a lean body phenotype caused by sustained activation of peroxisome proliferator-activated receptor α (PPARα) by endogenous ligands in liver that remain unmetabolized in the absence of Acox1. We generated ob/ob mice deficient in Acox1 (Acox1(-/-)) to determine how the activation of PPARα by endogenous ligands might affect the obesity of ob/ob mice. In contrast to Acox1(-/-) (14.3±1.2 g at 6 mo) and the Acox1-deficient (ob/ob) double-mutant mice (23.8±4.6 g at 6 mo), the ob/ob mice are severely obese (54.3±3.2 g at 6 mo) and had significantly more (P<0.01) epididymal fat content. The resistance of Acox1(-/-)/ob/ob mice to obesity is due to increased PPARα-mediated up-regulation of genes involved in fatty acid oxidation in liver. Activation of PPARα in Acox1-deficient ob/ob mice also reduces serum glucose and insulin (P<0.05) and improves glucose tolerance and insulin sensitivity. Further, PPARα activation reduces hepatic steatosis and increases hepatocellular regenerative response in Acox1(-/-)/ob/ob mice at a more accelerated pace than in mice lacking only Acox1. However, Acox1(-/-)/ob/ob mice manifest hepatic endoplasmic reticulum (ER) stress and also develop hepatocellular carcinomas (8 of 8 mice) similar to those observed in Acox1(-/-) mice (10 of 10 mice), but unlike in ob/ob (0 of 14 mice) and OB/OB (0 of 6 mice) mice, suggesting that superimposed ER stress and PPARα activation contribute to carcinogenesis in a fatty liver. Finally, absence of Acox1 in ob/ob mice can impart resistance to high-fat diet (60% fat)-induced obesity, and their liver had significantly (P<0.01) more cell proliferation. These studies with Acox1(-/-)/ob/ob mice indicate that sustained activation of lipid-sensing nuclear receptor PPARα attenuates obesity and restores glucose homeostasis by ameliorating insulin resistance but increases the risk for liver cancer development, in part related to excess energy combustion.

Project description:ObjectiveDetermine the impact of long-term non-surgical weight loss maintenance on clinical relevance for osteoarthritis, cancer, opioid use, and depression/anxiety and healthcare resource utilization.MethodsA cohort of adults receiving primary care within Geisinger Health System between 2001-2017 was retrospectively studied. Patients with ≥3 weight measurements in the two-year index period and obesity at baseline (BMI ≥30 kg/m2) were categorized: Obesity Maintainers (reference group) maintained weight within +/-3%; Weight Loss Rebounders lost ≥5% body weight in year one, regaining ≥20% of weight loss in year two; Weight Loss Maintainers lost ≥5% body weight in year one, maintaining ≥80% of weight loss. Association with development of osteoarthritis, cancer, opioid use, and depression/anxiety, was assessed; healthcare resource utilization was quantified. Magnitude of weight loss among maintainers was evaluated for impact on health outcomes.ResultsIn total, 63,567 patients were analyzed including 67% Obesity Maintainers, 19% Weight Loss Rebounders, and 14% Weight Loss Maintainers; median follow-up was 9.7 years. Time until osteoarthritis onset was delayed for Weight Loss Maintainers compared to Obesity Maintainers (Logrank test p <0.0001). Female Weight Loss Maintainers had a 19% and 24% lower risk of developing any cancer (p = 0.0022) or obesity-related cancer (p = 0.0021), respectively. No significant trends were observed for opioid use. Weight loss Rebounders and Maintainers had increased risk (14% and 25%) of future treatment for anxiety/depression (both <0.0001). Weight loss maintenance of >15% weight loss was associated with the greatest decrease in incident osteoarthritis. Healthcare resource utilization was significantly higher for Weight Loss Rebounders and Maintainers compared to Obesity Maintainers. Increased weight loss among Weight Loss Maintainers trended with lower overall healthcare resource utilization, except for hospitalizations.ConclusionsIn people with obesity, sustained weight loss was associated with greater clinical benefits than regained short-term weight loss and obesity maintenance. Higher weight loss magnitudes were associated with delayed onset of osteoarthritis and led to decreased healthcare utilization.

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Weight Cycling Increases Longevity Compared with Sustained Obesity in Mice.

Publications

Weight Cycling Increases Longevity Compared with Sustained Obesity in Mice.

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