Efficacy of Various Metformin Doses for the Restoration of Metabolic Indices and Hormonal Status in Early Weaned Male Rats

Early weaning (EW) leads to metabolic disorders in adulthood, being one of the causes of metabolic syndrome (MS). However, the range of hormonal disorders in EW has not been studied well enough, and approaches to its correction have not been developed. The aim of this work was to study metabolic and hormonal changes, including in the hormonal status of the gonadal and thyroid axes, in adult (10-month-old) male rats that were weaned in the early postnatal period, as well as to explore the restorative effect of 4-week treatment with different doses of metformin (MF), moderate (120 mg/kg/day) and relatively high (250 mg/kg/day), on these changes. Lactation in nursing female rats was interrupted with bromocriptine (10 mg/kg/day) on days 19–21 of lactation. After forced starvation during this period, rat pups were transitioned to a standard diet. At the age of 10 months, early weaned male rats showed characteristic signs of MS, such as obesity, impaired glucose tolerance, insulin resistance, hyperleptinemia and dyslipidemia. They also had reduced levels of testosterone, luteinizing hormone (LH), and thyroid hormones, and elevated levels of the thyroid-stimulating hormone (TSH). A 4-week treatment of adult rats with MF at a moderate dose reduced body and fat weight, partially restored metabolic parameters, and completely normalized testosterone, LH, thyroxine, triiodothyronine and TSH levels. The treatment with MF at a relatively high dose restored metabolic parameters more effectively, normalized leptin and insulin levels, but had a little effect on hormonal levels of the gonadal and thyroid axes. Thus, long-term treatment of early weaned male rats with a moderate dose of MF improves metabolic parameters and completely restores the hormonal status of the gonadal and thyroid axes, which indicates the promise of using such doses for the correction of MS and endocrine dysfunctions caused by interrupted or ineffective breastfeeding.