Suplementação de melatonina em mães obesas: Efeitos na ilhota pancreática, tecido adiposo branco e marrom, e hipotálamo na prole adulta de machos

Abstract

The study was designed to investigate the potential effects of melatonin supplementation in obese mothers on the health of their offspring in adulthood. Methods: Female C57Bl/6 mice (mothers) were divided into two groups based on diet: control (C, 17% kJ lipid) or high-fat (HF, 49% kJ lipid) and mated with males fed a control diet. During pregnancy and lactation, half of the C and HF mothers received daily melatonin supplementation (10 mg/kg), while the other half received an equal volume of vehicle, forming the groups C, CMel, HF, and HFMel (n=10/group). After weaning and until 12 weeks of age, offspring received only the C diet. Biometrics, plasma biochemistry, immunohistochemistry, gene expression in pancreatic islets, subcutaneous white adipose tissue (sWAT), and inter-scapular brown adipose tissue (iBAT), and protein and gene expression in the hypothalamus were analyzed. Results: HF mothers and their offspring showed higher body mass, glucose intolerance, insulin resistance, and lower insulin sensitivity compared to C mothers and their offspring. However, HFMel mothers and offspring showed significant improvements in glucose metabolism and reduced mass compared to HF mothers and offspring. In the pancreatic islets, increased pro-inflammatory and endoplasmic reticulum (ER) stress markers were observed in HF offspring, with reductions in HFMel offspring, and antioxidant enzymes were less expressed in HF offspring but increased in HFMel offspring. Additionally, there was an increase in beta-cell mass and hypersecretion of insulin in HF offspring, while HFMel offspring showed a decrease in these parameters. Comparing HFMel offspring to HF offspring, there was a reduction in fat deposits and plasma pro-inflammatory markers, and sWAT adipocytes exhibited a beige phenotype, accompanied by activation of the beta-3 adrenergic receptor and UCP-1, indicative of iBAT thermogenic activity. HFMel offspring also showed a reduction in neuroinflammation markers in the hypothalamus, with a diminished gene and protein expression in neuropeptide Y (anabolic) and augmented gene expression of proopiomelanocortin (catabolic) expression. Principal component analysis (PCA) separated HF offspring from HFMel offspring, indicating the benefit of maternal melatonin supplementation. Conclusion: The beneficial effects of melatonin supplementation in mothers with obesity were reflected in adult offspring in more suitable pancreatic islet remodeling and function, with reduced inflammation, oxidative stress, and ER stress, resulting in better control of glucose and insulin levels in pancreatic islets. Additionally, melatonin contributed to increased sWAT browning, enhanced iBAT thermogenesis, and mitigated inflammation in the hypothalamus and appetite-regulating neurotransmitters.