Obesity-associated alterations in adipokine concentrations, namely leptin and adiponectin, underpin the development of adipose tissue dysfunction, thus supporting an environment conducive to cardiometabolic disease [1, 2]. The purpose of this ancillary study was to investigate the relationship between the AL ratio, an emerging biomarker of adipose tissue dysfunction, and cardiometabolic health among older adults with obesity following a 12-month exercise and diet intervention

Previous research has consistently supported the relationship between AL ratio and cardiometabolic health among diverse populations including Korean, Japanese, Hispanic, and Slovenian adults [11, 22,23,24,25]. However, to our knowledge, this is the first study investigating the AL ratio in a biracial population of older adults. Results demonstrated that among older adults with obesity, the AL ratio was significantly associated with measures of adiposity and cardiometabolic health at baseline. In particular, correlations were observed between this ratio and BMI, WC, and measures of fat mass, as well as insulin, HDL-c, and inflammatory biomarkers. The inverse correlations related to adiposity suggest that the conventional obesity-associated alterations in adipokine secretion are captured by the AL ratio in this unique population. Similar correlations between AL ratio and body composition have been reported in Japanese adults with and without diabetes, as well as generally healthy Korean and Chinese adults [10, 22, 23, 26].

Results from the current study also support the AL ratio as a measure of adipose tissue dysfunction in the older adult population. For example, inverse correlations between this ratio and inflammatory biomarkers and insulin levels were observed, as well as a positive correlation with HDL-c. A surplus of circulating leptin nullifies its anorexigenic effects while concurrently amplifying its pro-inflammatory properties through increased activation of the nuclear factor kappa B (NFkB) signaling cascade [5, 27]. Furthermore, reductions in adiponectin inhibit signaling pathways to combat inflammation, thus perpetuating the pro-inflammatory response observed in obesity [6]. Previous research has also established a link between the AL ratio and inflammatory biomarkers, namely hsCRP and serum amyloid A (SAA), among Caucasian adults with and without metabolic syndrome [28]. Although SAA was not evaluated in the current study, this protein has been shown to increase proportionally with adiposity levels and to be responsive to weight loss interventions [29]. Accordingly, its incorporation into future investigations of the AL ratio and cardiometabolic health is warranted.

The relationship between AL ratio and insulin levels is likely driven by adiponectin. The binding of adiponectin to receptors in the liver and skeletal muscle activates signaling molecules like AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (p38 MAPK) thereby regulating glucose metabolism and insulin sensitivity [5, 7]. Zalatel et al. reported that the AL ratio was significantly associated with the euglycemic clamp-derived sensitivity index, a gold standard of insulin sensitivity assessment, and was also superior to other measures of insulin resistance, including homeostatic model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) index [11]. Strong correlations between the AL ratio and insulin levels have also been highlighted in Asian populations with and without hyperglycemia [10, 23].

Interestingly, among the lipids assessed, a significant correlation was only observed between AL ratio and HDL-c. The directionality of this relationship remains under investigation, but it is proposed that increased HDL-c enhances adiponectin secretion from adipose tissue, supporting its anti-inflammatory and insulin-sensitizing roles [30]. Nonetheless, similar relationships between the AL ratio and HDL-c have been reported [10, 14, 23]. Although previous research has not established a significant link between this ratio and LDL-c, there have been reports of an inverse correlation between AL ratio and TG levels [10, 14, 22, 23]. Such findings were not observed in the current study and may be related to a limited power to detect associations.

Acknowledging the differences in adipose tissue biology between males and females, it is suggested that biological sex be taken into account when investigating adiposity and cardiometabolic health [31]. The current study substantiates such recommendations, as males had a significantly higher AL ratio than females, irrespective of timing or intervention. Similar differences have been reported, albeit limited, and have been ascribed to inherent alterations in adipokine secretion between biological sexes [24, 25]. In general, circulating leptin levels tend to be higher among females with and without obesity compared to their male counterparts [32]. This is attributed, in part, to an increased rate of leptin secretion per unit mass of adipose tissue in females, as well as an influence of sex hormones on the release of adipokines [32, 33]. While additional mechanisms underpinning this discrepancy remain to be fully elucidated, results from the current study suggest that the AL ratio may be more sensitive to change among males.

There are a limited number of studies investigating the sensitivity of AL ratio to lifestyle interventions, and the few that exist were conducted among adolescents. For example, Masquio et al. enrolled adolescents with and without metabolic syndrome into a one-year study investigating the effects of combined nutrition and physical activity intervention on cardiometabolic health [34]. Both groups (no metabolic syndrome vs. overt metabolic syndrome) experienced an improvement in AL ratio that was associated with increases in omega-3 fatty acid consumption. Ferreira et al. implemented a non-intensive interdisciplinary therapy consisting of nutrition and exercise modifications among adolescents with obesity for 20 weeks [35]. In contrast to the first study, a significant increase in AL ratio was only observed among participants who lost >5% of body weight. While this magnitude of weight loss is generally accepted among the studied population, there is greater controversy surrounding such recommendations for older adults [36, 37]. Accordingly, the CROSSROADS parent study implemented a moderate weight loss intervention based upon recommendations outlined in a Position Statement by the American Society for Nutrition and The Obesity Society [18]. Adherence to this intervention resulted in a significant 4.1% reduction in body weight with preservation of lean body mass and bone mineral density [16]. Given the modest body weight changes observed in the current study compared to that achieved by Ferreira et al., it was unclear whether the AL ratio would be altered to a similar degree [35]. Nonetheless, the significant treatment effect observed in the current study demonstrates how each lifestyle intervention under investigation resulted in modification of the AL ratio to varying extents among older adults with obesity.

Despite overall improvements, expanded analysis of the interaction effects revealed that only participants in the exercise + weight maintenance group and exercise + weight loss group exhibited a significant increase in AL ratio from baseline to 12 months. Thus, while physical activity may influence adipokine secretion, results suggest that its benefits are amplified when combined with improvements in dietary quality and a caloric restriction of 500 kcal/d.

It is noteworthy that AL ratio benefits were observed in the exercise + weight maintenance group, as this underscores the importance of simple dietary modifications for the older adult population. Previous research suggests that certain nutrients, namely omega-3 fatty acids and fiber, may favorably alter the AL ratio [15, 38]. Although the purpose of this study was not to tease apart the individual dietary components associated with AL ratio changes, the results support how general improvements in dietary quality can have a meaningful impact on cardiometabolic health independent of weight loss. As such, recommendations to increase the consumption of fruit and non-starchy vegetables should not be underestimated by health care providers [16].

Though physical activity and dietary modifications may influence adipokine secretion, results from the current study suggest that an exercise + weight loss intervention is optimal for improved AL ratio in a community-dwelling older adult population with obesity. This is not unexpected, as weight loss is related to the restoration of balance in adiponectin and leptin levels, therefore supporting an increase in the AL ratio. These results, paired with the retention of lean body mass and bone mineral density, highlight the value of a comprehensive weight loss plan including a moderate caloric reduction and robust exercise program comprised of aerobic and resistance training.

Strengths of this study include robust outcome measures, notably the evaluation of visceral adipose tissue, as well as the rigorous design and monitoring of adherence in the parent study. This is also the first study to characterize the AL ratio as a measure of adipose tissue dysfunction and to evaluate its sensitivity to lifestyle interventions in a biracial older adult population. This study provides insightful results for future research, yet it is not exempt from some limitations. For example, this exploratory study was ancillary to a randomized controlled trial that was not specifically powered to detect the outcomes of this study, thus potentially obscuring some relationships. As such, an expanded investigation is warranted to discern potential differences in sensitivity of the AL ratio to lifestyle interventions by biological sex. Additionally, to enhance generalizability, it would be advantageous to evaluate the AL ratio among a greater number of Caucasian and African American older adults from various regions of the United States.