Changes in adiponectin:leptin ratio among older adults with obesity following a 12-month exercise and diet intervention

The study addresses whether the adiponectin:leptin (AL) ratio reflects adipose tissue dysfunction and cardiometabolic risk among older adults with obesity, and whether a 12-month exercise and diet intervention can improve the AL ratio. Obesity alters adipokine secretion—increasing leptin and reducing adiponectin—contributing to inflammation, insulin resistance, and dyslipidemia. The AL ratio has emerged as a potentially stronger indicator of adipose tissue dysfunction than either adipokine alone, but evidence in older adults and responsiveness to lifestyle interventions are limited. The authors hypothesized that the AL ratio would be inversely associated with adiposity and adverse cardiometabolic biomarkers (insulin/glucose dynamics, lipids, inflammation) and that exercise with diet quality improvements plus intentional weight loss would yield the greatest improvement in AL ratio compared with exercise alone or exercise plus diet quality without weight loss.

Prior work shows the AL ratio correlates more strongly than individual adipokines with inflammation, insulin resistance, oxidative stress, and cardiometabolic risk factors across various populations (Korean, Japanese, Hispanic, Slovenian). The ratio has been linked to euglycemic clamp-derived insulin sensitivity and may outperform indices like HOMA-IR and QUICKI. Associations with HDL cholesterol are reported, while links to LDL cholesterol are inconsistent and triglycerides may be inversely related in some studies. Sex differences in adipokine biology suggest the AL ratio may differ by biological sex, with women typically exhibiting higher leptin levels. Few studies have examined AL ratio responsiveness to lifestyle interventions, with existing adolescent studies suggesting improvements linked to diet quality (e.g., omega-3 intake) and weight loss magnitude. Evidence in older adults is scarce, creating a need to evaluate AL ratio as a biomarker and its sensitivity to combined exercise and dietary interventions in this demographic.

Design: Ancillary analysis of the CROSSROADS randomized controlled trial (ClinicalTrials.gov NCT00955903) among community-dwelling adults aged ≥65 years with obesity. Participants: Inclusion required BMI 30–40 kg/m² and use of at least one medication for lipids, blood pressure, or blood glucose, indicating cardiometabolic disease risk. Exclusions included medical, physical, or psychiatric limitations precluding intervention adherence or confounding weight changes. IRB approvals obtained (UAB and UA), with written informed consent. Randomization and groups: Stratified by age (65–74, ≥75 years), biological sex, and race, then block-randomized to: (1) Exercise only; (2) Exercise + nutrient-dense weight maintenance (exercise + weight maintenance); (3) Exercise + nutrient-dense caloric restriction of 500 kcal/d (exercise + weight loss). Data collectors were blinded to group assignment. Interventions: - Exercise (all groups): Standardized program combining aerobic (90–150 min/week moderate-to-vigorous) and resistance training (two sessions/week) using resistance bands; mix of home- and gym-based activities. Heart rate monitors provided; one supervised resistance session weekly; adherence tracked via diaries and accelerometry. - Diet counseling (weight maintenance and weight loss groups): Registered dietitian nutritionist delivered sessions weekly for 6 months, then biweekly. Emphasis on time–calorie displacement with increased low-energy-dense fruits/vegetables, lean protein, whole grains; macronutrient targets: 25% protein, 47% carbohydrate, 28% fat. Daily calorie goals based on baseline measured resting metabolic rate-derived total energy expenditure; weight loss group prescribed 500 kcal/d deficit. Dietary adherence assessed by three unannounced 24-h recalls (multi-pass), analyzed with NDSR. Outcomes and measurements (baseline and 12 months): - Biochemical cardiometabolic markers: fasting insulin, glucose, lipid panel, hsCRP (turbidimetric assays, SIRRIS analyzer), TNF-α and IL-6 (electrochemiluminescence), adiponectin and leptin (radioimmunoassay). AL ratio computed as adiponectin (µg/mL) / leptin (ng/mL). - Adiposity: Abdominal adipose tissue (intra-abdominal, subcutaneous, total abdominal volume) via 3T MRI; total and trunk fat mass (%) via DXA (Lunar DPX-L). Anthropometrics: BMI, waist circumference. - Blood pressure: Automated devices, duplicate measures averaged. Statistical analysis: SAS 9.4. Descriptives as mean ± SD or median [25th, 75th]. Mann–Whitney U and Spearman correlations assessed baseline relationships of AL ratio with cardiometabolic health, by biological sex due to sex differences. Intervention effects on AL ratio evaluated with generalized linear mixed models (PROC GLIMMIX), controlling for biological sex. Given right-skewed AL ratio distribution, negative binomial error with log link used; unstructured variance-covariance parameterized via Cholesky root; degrees of freedom by containment; random effects modeled via R-side within-subject variance. Multiple comparisons adjusted using Tukey–Kramer method. Significance at p < 0.05.

Participants: N = 163 (age 70.2 ± 4.7 years; 38.0% male; 23.5% African American). Randomized: exercise n=53; exercise + weight maintenance n=55; exercise + weight loss n=55. Completers: 147 (51, 47, 49 respectively). Baseline AL ratio differed by sex: males 0.33 [0.21, 0.61], females 0.19 [0.12, 0.29], p < 0.001. Baseline correlations (Spearman): - Males: AL ratio inversely correlated with BMI (r = -0.357, p = 0.004), waist circumference (r = -0.259, p = 0.044), DXA total fat % (r = -0.268, p = 0.035), DXA trunk fat % (r = -0.342, p = 0.007); insulin (r = -0.542, p < 0.001). No significant correlations with HDL-c, LDL-c, TG, hsCRP, IL-6. - Females: AL ratio inversely correlated with BMI (r = -0.471, p < 0.001), waist circumference (r = -0.385, p < 0.001), SAAT (r = -0.226, p = 0.026), total abdominal fat volume (r = -0.293, p = 0.003); insulin (r = -0.571, p < 0.001); hsCRP (r = -0.328, p = 0.001); IL-6 (r = -0.258, p = 0.010). Positively correlated with HDL-c (r = 0.395, p < 0.001). Intervention effects (GLMM): - Main effects: Time F(1,140) = 40.89, p < 0.0001 (AL ratio increased over 12 months); Intervention F(2,157) = 3.42, p = 0.035; Biological sex F(1,157) = 50.98, p < 0.0001 (males > females). - Interactions: Intervention × time F(2,140) = 21.32, p < 0.0001; Intervention × sex F(2,157) = 4.44, p = 0.013; Sex × time F(1,140) = 5.84, p = 0.017; three-way interaction ns (p = 0.563). - Within-group changes: Exercise + weight maintenance: adjusted mean AL ratio increased from 0.327 to 0.361 (p = 0.027). Exercise + weight loss: increased from 0.357 to 0.511 (p < 0.001). Exercise-only group did not show significant increase. - Between-group at 12 months: Exercise + weight loss had significantly greater AL ratio vs exercise + weight maintenance (p < 0.001) and exercise-only (p = 0.004). Change–change associations: Improvements in AL ratio correlated with reductions in adiposity measures, notably intra-abdominal adipose tissue in the weight loss group (r = -0.620, p < 0.001), total abdominal fat volume in weight maintenance (r = -0.323, p = 0.033) and weight loss (r = -0.456, p = 0.002), and DXA trunk fat % in weight maintenance (r = -0.405, p = 0.006) and weight loss (r = -0.423, p = 0.003).

Findings support the AL ratio as an indicator of adipose tissue dysfunction and cardiometabolic risk in older adults with obesity. The inverse associations with adiposity, insulin, and inflammatory markers, alongside positive association with HDL-c (in females), align with the hypothesized role of adiponectin and leptin in metabolic homeostasis. Sex differences were evident, with males exhibiting higher AL ratios across time and interventions, consistent with known sex-related adipokine differences; this suggests consideration of biological sex in interpretation and potential responsiveness of AL ratio. Intervention results indicate that exercise alone may be insufficient to meaningfully improve AL ratio over 12 months in this population, whereas combining exercise with diet quality improvements increases the AL ratio, and the addition of a modest caloric restriction (500 kcal/d) with resultant intentional weight loss yields the greatest improvement. Improvements in AL ratio tracked with reductions in central adiposity, particularly intra-abdominal fat, underscoring the metabolic relevance of visceral fat reduction. These outcomes address the study hypothesis by demonstrating both cross-sectional validity of AL ratio with cardiometabolic health and longitudinal responsiveness to lifestyle intervention, highlighting its potential clinical utility to monitor adipose tissue function and cardiometabolic risk mitigation strategies in older adults.

The AL ratio correlates with adiposity and cardiometabolic biomarkers in older adults with obesity, supporting its use as a biomarker of adipose tissue dysfunction and cardiometabolic risk. A 12-month exercise and diet intervention, particularly when incorporating intentional weight loss via moderate caloric restriction alongside aerobic and resistance training, optimally improves the AL ratio. Including the AL ratio in future obesity research and clinical assessments may aid in identifying individuals at risk and monitoring response to lifestyle interventions. Future work should further explore sex-specific responsiveness and broaden demographic representation.

As an ancillary, exploratory analysis, the parent randomized controlled trial was not specifically powered for these AL ratio outcomes, potentially limiting detection of some associations. Sex-specific sensitivity differences warrant further investigation. Generalizability may be limited by the regional sample; inclusion of larger and more diverse cohorts of older adults (e.g., broader representation of Caucasian and African American participants across U.S. regions) is needed. The study did not dissect specific dietary components driving AL ratio changes.