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Exercise training markedly augments dietary weight loss-induced improvements in multi-organ system metabolic function in people with obesity and prediabetes

ABSTRACT: The additional therapeutic effects of regular exercise during a dietary weight loss program in people with obesity and prediabetes are unclear. We evaluated the effect of 10% weight loss, induced within ~5 months by calorie-restriction alone (Diet-ONLY, n=8) or calorie-restriction plus multi-modal exercise training (Diet+EX, n=8), on metabolic function in people with obesity and prediabetes. Whole-body (primarily muscle) and hepatic insulin sensitivity were 2-3 fold greater in the Diet+EX than the Diet-ONLY group, and were accompanied by increased muscle expression of genes involved in mitochondrial biogenesis, energy metabolism and angiogenesis in the Diet+EX group without any change in the Diet-ONLY group. There were no differences between groups in plasma branched-chain amino acids or markers of inflammation, and both interventions caused similar changes in the gut microbiome. These results demonstrate that adding regular exercise to a diet-induced weight loss program has profound metabolic benefits in people with obesity and prediabetes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230002 | GEO | 2023/04/26

REPOSITORIES: GEO

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Project description:Background. Differential gene expression in adipose tissue during diet-induced weight loss followed by a weight stability period is not well characterized. Markers of these processes may provide a deeper understanding of the underlying mechanisms. Objective. To identify differentially expressed genes in human adipose tissue during weight loss and weight maintenance after weight loss. Design. RNA from subcutaneous abdominal adipose tissue from nine obese subjects was obtained and analyzed at baseline, after weight reduction on a low calorie diet (LCD), and after a period of group therapy in order to maintain weight stability. Results. Subjects lost 18.8 + 5.4% of their body weight during the LCD and maintained this weight during group therapy. Insulin sensitivity (HOMA) improved after weight loss with no further improvement during weight maintenance. Cyclin-dependent kinase inhibitor 2B (CDKN2B) and JAZF zinc finger 1 (JAZF1), associated with type 2 diabetes, were downregulated. We could also confirm the downregulation of candidates for obesity and related traits, such as tenomodulin (TNMD) and matrix metallopeptidase 9 (MMP9), with weight loss. The expression of other candidates, such as cell death-inducing DFFA-like effector A (CIDEA) and stearoyl-CoA desaturase (SCD) were upregulated during weight loss but returned to baseline levels during weight maintenance. Conclusion. Genes in the adipose tissue are differentially expressed during weight loss and weight maintenance after weight loss. Genes that show sustained regulation may be of potential interest as markers of the beneficial effects of weight loss whereas others seem to be primarily involved in the process of weight loss itself. Nine participants were prescribed a low calorie diet (LCD) containing 1200 kcal/day for approximately three months (101 ± 26 days). Following the weight reduction phase the participants attended a six month follow-up period (167 ± 37 days). By protocol design, subjects were eligible to enter the study if they had lost at least 10% of their initial body weight during the LCD-period and maintained this weight (+5%) after group therapy. Subcutaneous adipose tissue samples were obtained at three time-points: (i) at baseline, (ii) after weight reduction when subjects were no longer losing weight, and (iii) after the group therapy weight maintenance phase.

Project description:Background: Moderate weight loss can ameliorate adverse health effects associated with obesity, reflected by an improved adipose tissue (AT) gene expression profile. However, the effect of rate of weight loss on the AT transcriptome is unknown. Objective: We investigated the global AT gene expression profile before and after two different rates of weight loss that resulted in similar total weight loss, and after a subsequent weight stabilization period. Design: In this randomized controlled trial, 25 male and 28 female individuals (BMI: 28-35 kg/m2) followed either a low-calorie diet (LCD; 1250 kcal/d) for 12 weeks or a very-low-calorie diet (VLCD; 500 kcal/d) for 5 weeks (weight loss (WL) period) and a subsequent weight stable (WS) period of four weeks. The WL period and WS period together is termed dietary intervention (DI) period. Abdominal subcutaneous AT biopsies were collected for microarray analysis, and gene expression changes were calculated for all three periods in the LCD group, VLCD group and between diets (ΔVLCD-ΔLCD). Results: Weight loss was similar between groups during the WL period (LCD: -8.1±0.5 kg, VLCD: -8.9±0.4 kg, difference p=0.25). Overall, more genes were significantly regulated and changes in gene expression were more extreme in the VLCD group compared to the LCD group. Gene sets related to mitochondrial function, adipogenesis and immunity/inflammation were more strongly upregulated on a VLCD compared to a LCD during the DI period (positive ΔVLCD-ΔLCD). Neuronal- and olfactory-related gene sets were decreased during the WL period and DI period in the VLCD group. Conclusions: The rate of weight loss (LCD vs. VLCD), with similar total weight loss, strongly regulates AT gene expression. Increased mitochondrial function and adipogenesis on a VLCD compared to a LCD reflect potential beneficial diet-induced changes in AT, while differential neuronal and olfactory regulation suggest functions of these genes beyond the current paradigm.

Project description:Objective Obesity is a multidimensional condition that is treatable by the restoration of a lean phenotype; however, some obesity-related outcomes may persist after weight normalization. Among the organs of the human body, the brain possesses a relatively low regenerative capacity and could retain perturbations established as a result of developmental obesity. Calorie restriction (CR) or a restricted ketogenic diet (KD) are successfully used as weight loss approaches, but their impact on obesity-related effects in the brain have not been previously evaluated. Methods We performed a series of experiments in a rat model of developmental obesity induced by a 12-week cafeteria diet, followed by CR to implement weight loss. First, we assessed the impact of obesity on neurogenesis (BrdU incorporation into the hippocampus), cognitive function (water maze), and concomitant changes in hippocampal protein expression (GC/MS-MS, western blot). Next, we repeated these experiments in a rat model of weight loss induced by CR. We also measured mitochondrial enzyme activity in rats after weight loss during the fed or fasting state. By using a modified version of the water maze we evaluated cognitive abilities in rats subjected to weight loss by CR or a restricted KD. Results In this study, obesity affected metabolic processes, upregulated hippocampal NF-κB, and induced proteomic differences which were associated with impaired cognition and neurogenesis. Weight loss improved neurogenesis and enhanced cognition. While the expression pattern of some proteins persisted after weight loss, most of the changes appeared de novo revealing metabolic adjustment by overactivation of citrate synthase and downregulation of ATP synthase. As a consequence of fasting, the activity of these enzymes indicated hippocampal adaptation to negative energy balance during the weight loss phase of CR. Moreover, the effects on cognitive abilities measured after weight loss were negatively correlated with the obesity level and were alleviated by KD, which improved cognition when used as a weight loss approach. Conclusions The study shows that cognition and mitochondrial metabolism in the hippocampus are affected by CR- or KD-induced weight loss.

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Exercise training markedly augments dietary weight loss-induced improvements in multi-organ system metabolic function in people with obesity and prediabetes

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