Melatonin-Supplemented Obese Female Mice Show Less Inflammation in Ovarian Adipocytes and Browning in Subcutaneous Adipocytes

We hypothesized that melatonin (Mel) supplementation may offer therapeutic benefits for obesity, particularly in women. Therefore, the study evaluated Mel's effects on white adipose tissue (WAT) in diet-induced obese female mice. Four-week-old C57BL/6 females were assigned to either a control diet (C group) or a high-fat diet (HF group) for 6 weeks (n = 20/group). Following this, Mel was administered (10 mg/kg/day) for 8 weeks (n = 10/group), resulting in four groups: C, CMel, HF, and HFMel. The HF group developed obesity. HFMel displayed reduced fat pad size, lower plasma insulin, and improved glucose tolerance and insulin resistance compared to HF. In ovarian WAT (oWAT), HFMel versus HF showed reduced pro-inflammatory markers, less endoplasmic reticulum (ER) stress, and smaller adipocyte size. In subcutaneous WAT (sWAT), HFMel versus HF demonstrated increased adipocyte multiloculation, higher uncoupling protein-1 expression, and elevated thermogenic gene expression. Principal component analysis of gene expressions in oWAT and sWAT revealed significant differences: in oWAT, ER stress and inflammation markers were linked to the HF group, while HFMel and CMel clustered together, indicating a beneficial Mel effect. In sWAT, HFMel and CMel clustered on the opposite side of HF, which is associated with thermogenic gene expressions. In conclusion, the findings demonstrate that Mel supplementation in obese female mice, even when maintained on an HF diet, effectively modulated weight gain and reduced ovarian and subcutaneous fat accumulation. Mel supplementation positively influenced insulin resistance, inflammation, and ER stress while promoting thermogenesis in WAT in obese female mice.