The Important Role of Intermuscular Adipose Tissue on Metabolic Changes Interconnecting Obesity, Ageing and Exercise: A Systematic Review

As age increases, adipose tissue infiltrates muscle tissue and leads to sarcopenia. When excessive accumulation of adipose tissue accompanied progressive decrease in lean body mass especially visceral fat, termed as sarcopenic obesity (SO) and related metabolic intermuscular adipose tissue (IMAT) is an ectopic tissue found between muscle groups, and is distinct from subcutaneous adipose tissue. Until now, the association between IMAT and metabolic health was not understood. This study is the first systematic review assessing the association between IMAT and metabolic health. The PubMed, Science Direct and Cochrane databases were searched for studies reporting IMAT and metabolic risk. The descriptions of the extracted data are guided by the Preferred Reporting Items for Systematic Reviews (PRISMA) statement with a Grading of Recommendations Assessment, Development and Evaluation approach. This study is registered at PROSPERO (identifier: CRD42022337518). Six studies were pooled and reviewed using critical appraisal by the Newcastle Ottawa Scale and Centre for Evidence-Based Medicine checklist. Two clinical trials and four observational trials were included. Our results reveal that IMAT is associated with metabolic risk, especially in older adults and patients with obesity. However, in a person with abdominal obesity, VAT has a more significant role in metabolic risk than IMAT. The largest decrease in IMAT was achieved by combining aerobic with resistance training.

Obesity is related to an increased risk of metabolic disease. 1 It is well established that excessive body fat is related to increased morbidity and mortality and is associated with inflammation and endothelial damage. 2,3 With age, fat infiltration occurs in the muscle, leading to sarcopenia.
The association of the excessive accumulation of adipose tissue with a progressive decrease in lean body mass, especially visceral fat, is termed sarcopenic obesity (SO). 4,5 Adipose tissue is classified into subcutaneous adipose tissue (SAT) and ectopic adipose tissue. Ectopic adipose tissue is pathological.
Intermuscular adipose tissue (IMAT) is one of ectopic adipose tissue beside visceral adipose tissue. IMAT is directly related to increasing risk of insulin resistance, subclinical atherosclerosis, metabolic syndrome and cardiovascular disease. [6][7][8][9][10] Adipokines such as monocyte chemoattractant protein-1 (MCP-1), leptin and adiponectin are secreted from IMAT and play a critical role in obesity-related insulin resistance, altered lipid metabolism and inflammatory response. 11,12 IMAT accretion is mostly described in degenerative muscular disorders associated with age; however, it has also been seen in chronic conditions associated with a decline in physical activity due to reduced muscle contractile function. 13 Exercise training may lessen the overall amount of fat deposited in tissues and organs and of adipose tissue, including IMAT. 14 Until now, studies associating IMAT and metabolic change is not yet clear due to inconsistent result of studies. This study is the first systematic review to investigate the association between IMAT and metabolic syndrome.

Eligibility criteria
Eligible publications were screened independently by the authors.
Inclusion criteria were articles 1) written in the English language, 2) published in 2012 or later and 3) reporting a clinical trial or observational study. Letters, viewpoints and reviews that provided further insight into IMAT and metabolic parameters were excluded. Included studies reported the association between IMAT and metabolic syndrome.
Cardiovascular and metabolic parameters, namely MCP-1 and insulin sensitivity index (ISI) and metabolic syndrome risk, were assessed. The Japanese criteria for metabolic syndrome included a special criteria for high waist circumference of ≥85 cm in men and ≥90 cm in women but not high body mass index (BMI ≥25 kg/m 2 ) due to the unique anthropometricy seen in the Japanese population.

Search strategy
The literature review was carried out using the keywords "(Intermuscular Adipose Tissue) AND (metabolic syndrome)" in the PubMed, Science Direct and Cochrane Central Register of Controlled Trials databases ( Table 1). [15][16][17] Data extraction and assessment All references were reviewed using the critical appraisal Newcastle-Ottawa Scale 18 and the Centre for Evidence-Based Medicine checklist. 19 Each author independently reviewed all titles and abstracts to identify irrelevant studies. The titles and abstracts of articles were used to select those eligible for the first screening based on the established inclusion and exclusion criteria and were screened for articles reporting IMAT and metabolic syndrome. Articles that passed the first screening were checked in full to identify those relevant to the relationship between IMAT and metabolic syndrome. Articles that did not meet the inclusion criteria were eliminated. The authors' names, year of publication, sampling period, study location, sample size, study design, age range of participants,

Study characteristics
The literature search results and study selection process are presented in Figure 1. Before screening, 305 duplicate records and 19 records marked ineligible by automation tools were removed. Then, 124 articles were excluded because they did not assess metabolic parameters or they were animal studies and viewpoints and review studies. Ten potential articles were chosen to undergo full assessment for eligibility in the current review. Finally, the systematic review, included six publications on the impact of IMAT on metabolic parameters: four observational trials and two clinical trials. In Table 2 and Table 3, an overview and critical evaluation of studies that qualified for the systematic review are described. The level of evidence by GRADE was low to moderate due to the suboptimal quality of research. [21][22][23][24][25][26]

Discussion
Adults who are obese VAT, SAT and high-density muscle in a multivariate analysis (β=0.433, p=0.001). 23 Low-density muscle were considered as areas that had attenuation values between 0 and 34 HU, which indicates fat-rich muscle, while the areas that had attenuation values between 35 and 100 were regarded as high-density muscle, which indicates normal muscle.
MCP-1 is one of the major adipokines secreted by adipose macrophages as well as a proinflammatory cytokine that plays a role in metabolic dysfunction. 27 It helps recruit immune cells, such as macrophages and T cells, in the extracellular signal-regulated kinase pathway to increase insulin resistance. 6,28,29 Leptin is an adipokine derived from adipose tissue that contributes to inflammatory processes. 30,31 In one study, leptin messenger RNA (mRNA) was expressed more in older patients than in young patients. 32 Metabolically healthy obese individuals are also associated with better adipose tissue composition and capacity. 33 Haam et al. showed that MCP-1 levels were associated with increased levels of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and insulin. 23 However, the association between leptin levels and IMAT was found to be nonsignificant after adjustments for VAT, SAT and highdensity muscle (β=-0.051; p=0.686).

Middle-aged adults
Bang et al. studied 166 middle-aged and older Japanese adults without exercise habits or severe metabolic disease (mean age 68.9 ± 5.5 years; 53 men, 113 women). 21 Thigh muscle and abdominal cross-sectional The relationship between muscle, fat and insulin may be explained by increased intramyocellular lipid (IMCL)-associated insulin resistance and be related to low oxidative capacity. 38 Many previous studies have reported that oxidative capacity in skeletal muscle has a role in IMCL accumulation and insulin resistance. 39 Many previous studies have reported that oxidative capacity in skeletal muscle has a role in IMCL accumulation and insulin resistance. 38   The European Working Group on Sarcopenia in Older People defines sarcopenia as a syndrome with progressive and generalized loss of skeletal muscle mass and strength. 45 During the ageing process, muscle is depleted and replaced by fat. SO arises from the excessive accumulation of adipose tissue, especially visceral fat, and a decrease in lean body mass. 46 IMAT is an ectopic fat, and its accumulation promotes muscle lipid excess via interstitial free fatty acids. IMAT has been postulated to be associated with age and fatty infiltration into the skeletal muscle.
It may cause cytokine release which related to metabolic changes. 47 IMAT mRNA accumulation genes regulate lipolysis, insulin sensitivity and inflammatory cytokines such as MCP-1. 6

Post-menopausal adults
Goss and Gower studied 97 healthy, early post-menopausal women and assessed the relationship between insulin sensitivity and the subcompartments of thigh adipose tissue. 22 In this study, thigh IMAT and intra-abdominal adipose tissue (IAAT) were negatively associated with ISI. The highest correlation coefficients were between abdominal SAT and thigh SAT (r=0.73), IAAT and thigh IMAT (r=0.69), and IAAT and abdominal SAT (r=0.69). The correlation between ISI and thigh IMAT was negatively correlated in simple (r= -0.51; p<0.001) but not in multiple linear regression (standardized β=0.05 ; p=0.72). After adjusting for high IAAT, tight IMAT and ISI were found to be negatively correlated (standardized β=-0.8; p=0.01) . 22 Menopause predisposes women to weight gain and fat accumulation, especially visceral fat. 40  Our study is the first to systematically review of IMAT-related evidence to metabolic changes. Limited research has been conducted so far, and the included studies vary in outcomes, intervention and study design. There is no head-to-head comparison between each study.
The level of evidence by GRADE has been graded low to moderate due to the high risk of bias, inconsistency and uncertainty; therefore, the findings should be interpreted as low quality. More randomized controlled trials of IMAT and metabolic health are needed to provide better information and improve the quality of the review. It may also be meaningful to use a combination of VAT and IMAT as a marker of metabolic health and as a target for intervention.

Future directions and conclusions
IMAT is associated with metabolic syndrome risk, especially in older and adults who are obese. However, in people with abdominal obesity, VAT has a more significant role in metabolic syndrome than IMAT. IMAT decreased the most in participants that underwent combined aerobic and resistance exercise. We suggest the IMAT is screened and addressed in patients susceptible to metabolic syndrome to reduce the rates of metabolic events. q