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      Effects of exercise and dietary intervention on muscle, adipose tissue, and blood IRISIN levels in obese male mice and their relationship with the beigeization of white adipose tissue

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          Abstract

          Background

          Obesity is a growing problem worldwide, and newer therapeutic strategies to combat it are urgently required. This study aimed to analyze the effect of diet and exercise interventions on energy balance in mice and elucidate the mechanism of the peroxisome proliferator-activated receptor-gamma co-activator-1-alpha-IRISIN-uncoupling protein-1 (PGC-1α-IRISIN-UCP-1) pathway in the beigeization of white adipose tissue.

          Methods

          Four-week-old male C57BL/6 mice were randomly divided into normal (NC) and high-fat diet (HFD) groups. After 10 weeks of HFD feeding, obese mice were randomly divided into obesity control (OC), obesity diet control (OD), obesity exercise (OE), and obesity diet control exercise (ODE) groups. Mice in OE and ODE performed moderate-load treadmill exercises: for OD and ODE, the diet constituted 70% of the food intake of the OC group for 8 weeks.

          Results

          Long-term HFD inhibits white adipose tissue beigeization by downregulating PGC-1α-IRISIN-UCP-1 in the adipose tissue and skeletal muscles. Eight weeks of exercise and dietary interventions alleviated obesity-induced skeletal muscle, and adipose tissue PGC-1α-IRISIN-UCP-1 pathway downregulation promoted white adipose tissue beigeization and reduced body adipose tissue. The effects of the combined intervention were better than those of single interventions.

          Conclusions

          Diet and exercise intervention after obesity and obesity itself may affect the beigeization of WAT by downregulating/upregulating the expression/secretion of skeletal muscle and adipose PGC-1α-IRISIN, thereby influencing the regulation of bodyweight. The effects of the combined intervention were better than those of single interventions.

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          Most cited references43

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          A PGC1α-dependent myokine that drives browning of white fat and thermogenesis

          Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional coactivator PGC1α Here we show that PGC1α expression in muscle stimulates an increase in expression of Fndc5, a membrane protein that is cleaved and secreted as a new hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be a protein therapeutic for human metabolic disease and other disorders that are improved with exercise.
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            Cold-activated brown adipose tissue in healthy men.

            Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism. We studied 24 healthy men--10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], or = 25)--under thermoneutral conditions (22 degrees C) and during mild cold exposure (16 degrees C). Putative brown-adipose-tissue activity was determined with the use of integrated (18)F-fluorodeoxyglucose positron-emission tomography and computed tomography. Body composition and energy expenditure were measured with the use of dual-energy x-ray absorptiometry and indirect calorimetry. Brown-adipose-tissue activity was observed in 23 of the 24 subjects (96%) during cold exposure but not under thermoneutral conditions. The activity was significantly lower in the overweight or obese subjects than in the lean subjects (P=0.007). BMI and percentage of body fat both had significant negative correlations with brown adipose tissue, whereas resting metabolic rate had a significant positive correlation. The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity. 2009 Massachusetts Medical Society
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              Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance.

              Recently irisin (encoded by Fndc5 gene) has been reported to stimulate browning and uncoupling protein 1 expression in sc adipose tissue of mice. The objective of the study was to investigate FNDC5 gene expression in human muscle and adipose tissue and circulating irisin according to obesity, insulin sensitivity, and type 2 diabetes. Adipose tissue FNDC5 gene expression and circulating irisin (ELISA) were analyzed in 2 different cohorts (n = 125 and n = 76); muscle FNDC5 expression was also evaluated in a subcohort of 34 subjects. In vitro studies in human preadipocytes and adipocytes and in induced browning of 3T3-L1 cells (by means of retinoblastoma 1 silencing) were also performed. In both sc and visceral adipose tissue, FNDC5 gene expression decreased significantly in association with obesity and was positively associated with brown adipose tissue markers, lipogenic, insulin pathway-related, mitochondrial, and alternative macrophage gene markers and negatively associated with LEP, TNFα, and FSP27 (a known repressor of brown genes). Circulating irisin and irisin levels in adipose tissue were significantly associated with FNDC5 gene expression in adipose tissue. In muscle, the FNDC5 gene was 200-fold more expressed than in adipose tissue, and its expression was associated with body mass index, PGC1α, and other mitochondrial genes. In obese participants, FNDC5 gene expression in muscle was significantly decreased in association with type 2 diabetes. Interestingly, muscle FNDC5 gene expression was significantly associated with FNDC5 and UCP1 gene expression in visceral adipose tissue. In men, circulating irisin levels were negatively associated with obesity and insulin resistance. Irisin was secreted from human adipocytes into the media, and the induction of browning in 3T3-L1 cells led to increased secreted irisin levels. Decreased circulating irisin concentration and FNDC5 gene expression in adipose tissue and muscle from obese and type 2 diabetic subjects suggests a loss of brown-like characteristics and a potential target for therapy.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                11 February 2022
                01 March 2022
                : 11
                : 3
                : e210625
                Affiliations
                [1 ]School of Physical Education , Liaoning Normal University, Dalian, Liaoning, China
                [2 ]Exercise and Health Research Center , Department of Kinesiology, Laboratory Management Center, Shenyang Sport University, Shenyang, Liaoning, China
                [3 ]Department of Sports Medicine , School of Public and Basic Sciences, China Medical University, Shenyang, Liaoning, China
                Author notes
                Correspondence should be addressed to B Chang or S Cao: changbo8387@ 123456163.com or caoshicheng6666@ 123456163.com
                Author information
                http://orcid.org/0000-0003-3217-151X
                http://orcid.org/0000-0002-1024-0695
                Article
                EC-21-0625
                10.1530/EC-21-0625
                8942313
                35148278
                c0505ebd-bc54-43eb-8c9a-267b3ba3d44c
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 27 January 2022
                : 11 February 2022
                Categories
                Research

                obesity,white adipose beigeization,food restriction,pgc-1α-irisin-ucp-1

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