Caloric restriction improves glycemic control via the adiponectin–ceramide axis in non-obese men and women: the CALERIE™ 2 randomized controlled trial

Caloric restriction (CR) improves metabolic health across species, but the molecular mediators of its effects in humans remain incompletely defined. In a 24-month non-blinded randomized controlled trial (Clinicaltrial.gov: NCT00427193) of non-obese (BMI 22-27.9 kg/m2) men and premenopausal women aged 21 to 50 years, we assessed prespecified outcomes. Participants were randomized to an ad libitum or CR diet. We found that CR was associated with increased high-molecular-weight (HMW) adiponectin and reduced circulating ceramide species implicated in insulin resistance, including C16:0, C18:0, and C24:0. Mediation analysis indicated that reductions in ceramides were statistically compatible with partial mediation of the CR-associated improvements in insulin secretion, insulin sensitivity, and IGF-1 signaling markers. These effects were most pronounced at 12 months and attenuated by 24 months, suggesting partial metabolic adaptation over time. Overall, our findings are consistent with a model in which CR remodels bioactive lipid profiles and may enhance glucose metabolism in part through an adiponectin-ceramide-linked mechanism, highlighting a potential therapeutic axis for enhancing metabolic health. In the 24-month CALERIE randomized clinical trial, caloric restriction in non-obese adults increased HMW adiponectin and reduced insulin resistance–related ceramides, which is partially mediated by insulin sensitivity and IGF-1 signaling.