TRH and TRH-like peptide levels covary with caloric restriction and oral metformin in rat heart and testis

Obesity, type 2 diabetes, and major depression are common comorbidities in aging populations. Metformin (MF) mimics effects of caloric restriction (CR) which increases health and life spans. CR suppresses central TRH activity resulting in bradycardia and suppression of energy expenditure. TRH and TRH-like peptides with sequence pGlu-X-Pro-NH2, (X-TRH) where ‘X’ can be any amino acid residue, have anorectic, antidepressant, anxiolytic, analeptic, anti-epileptic, neuroprotective and anti-aging effects. The present studies compare the effects of CR and oral MF on expression of TRH and TRH-like peptides. CR experiment: Sixteen male Sprague-Dawley rats divided into 4 groups: ad libitum fed (CR-CON), 24 h fasted (CR-AC), fed (ADF1) or fasted (ADF2) 24 h after 10 days of alternate day fasting. MF experiment: Sixteen rats divided into 4 groups: water (MF-CON), 6 mg MF/ml water 24 h (MF-AC), 10 days MF (CHR) or 8 days MF then 48 h water (WD). Comparison of chronic MF and ADF2 treatment effects on TRH and TRH-like peptide levels in testis revealed a consistent pattern for peptide responses observed in the two experiments with Glu-TRH > Val-TRH > TRH > Peak 2 > Trp-TRH > Phe-TRH > Tyr-TRH. TRH levels increased in heart during CR and MF treatment consistent with cardiac responses to congestive heart failure and infarction. Because TRH reverses aging-induced testicular degeneration and mediates the pathophysiology of congestive heart failure these tripeptides may participate in the therapeutic effects of MF in ameliorating the cardiometabolic risk factors and fertility impairments associated with type 2 diabetes. •TRH levels in heart increased with CR and MF treatment supporting its involvement in cardiac responses to congestive heart failure and infarction.•CR and MF treatment both increased TRH levels in testis consistent with the anti-aging effects of this peptide in the reproductive system.•TRH and TRH-like peptide levels covary in testis in response to oral metformin and caloric restriction.•TRH and TRH-like peptides may participate in the therapeutic effects of caloric restriction and oral metformin.