Oxytocin Treatment Prevents the Cardiomyopathy Observed in Obese Diabetic Male db/db Mice

Abstract

Oxytocin (OT) is involved in the regulation of energy metabolism and in the activation of cardioprotective mechanisms. We evaluated whether chronic treatment with OT could prevent the metabolic and cardiac abnormalities associated with diabetes and obesity using the db/db mice model. Four-week-old male db/db mice and their lean nondiabetic littermates (db/+) serving as controls were treated with OT (125 ng/kg · h) or saline vehicle for a period of 12 weeks. Compared with db/+ mice, the saline-treated db/db mice developed obesity, hyperglycemia, and hyperinsulinemia. These mice also exhibited a deficient cardiac OT/natriuretic system and developed systolic and diastolic dysfunction resulting from cardiomyocyte hypertrophy, fibrosis, and apoptosis. These abnormalities were associated with increased reactive oxygen species (ROS) production, inflammation, and suppressed 5'-adenosine monophosphate kinase signaling pathway. The db/db mice displayed reduced serum levels of adiponectin and adipsin and elevated resistin. OT treatment increased circulating OT levels, significantly reduced serum resistin, body fat accumulation (19%; P<.001), fasting blood glucose levels by (23%; P<.001), and improved glucose tolerance and insulin sensitivity. OT also normalized cardiac OT receptors, atrial natriuretic peptide, and brain natriuretic peptide, expressions and prevented systolic and diastolic dysfunction as well as cardiomyocyte hypertrophy, fibrosis, and apoptosis. Furthermore, OT reduced cardiac oxidative stress and inflammation and normalized the 5'-adenosine monophosphate-activated protein kinase signaling pathway. The complete normalization of cardiac structure and function by OT treatment in db/db mice contrasted with only partial improvement of hyperglycemia and hyperinsulinemia. These results indicate that chronic treatment with OT partially improves glucose and fat metabolism and reverses abnormal cardiac structural remodeling, preventing cardiac dysfunction in db/db mice.

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

“…Those reports also did not include body weight or total fat mass following diet exposure in either HFD-fed rats or age-matched chow-fed control rats (23) but instead focused on the effects of chronic subcutaneous infusions of oxytocin on changes of body weight gain and body composition relative to vehicle treatment. Consistent with other studies (23,73), oxytocin treatment limited fat mass while eliciting either no Values are means Ϯ SE; n ϭ 5-6/group. FGF-21, fibroblast growth factor-21; FFA, free fatty acids.…”

“…One study reported that chronic subcutaneous administration of oxytocin, at a dose that reduced weight gain in obese db/db mice, also appeared to increase the number of uncoupling protein-1 (ϩ) cells in subcutaneous and visceral fat of obese db/db mice (73). Furthermore, Lawson and colleagues (48) demonstrated that oxytocin in amenorrheic athletes is positively correlated with resting energy expenditure as well as FGF-21 and irisin, two factors that induce the conversion of white adipose tissue to the "brite" or "beige" adipose tissue (14,28,98).…”

“…Moreover, the pathogenesis of PraderWilli syndrome, a rare human genetic disorder characterized by hyperphagia and severe obesity, is linked to a reduced size and number of PVN oxytocin neurons (91). Importantly, both acute and chronic administration of oxytocin is sufficient to bypass impaired leptin signaling to reduce weight gain or body weight in both DIO (23,53,59,103,104) and genetically obese rodent models (1,42,47,54,59,73) as well as weight loss in DIO rhesus monkeys (10) and humans (105). While collectively these findings are indicative of an important physiological role for oxytocin in energy homeostasis, the mechanisms underlying this function have not been fully elucidated.…”

“…Transgenic mice with deficient oxytocin (18) or oxytocin receptor (OTR) signaling (93) exhibit adult-onset obesity, and copy number variations associated with the OTR gene (OXTR) are linked with an early-onset obesity phenotype in humans (96). Furthermore, impaired oxytocin release within the hypothalamic paraventricular nucleus (PVN) is evident in dietinduced obese (DIO) mice (103), which could lead to defects in peripheral release of oxytocin, and potentially explain the decreased circulating levels in DIO mice (103,104), genetically obese rodents (32,73), as well as obese humans and individuals with Type 2 diabetes (74). Moreover, the pathogenesis of PraderWilli syndrome, a rare human genetic disorder characterized by hyperphagia and severe obesity, is linked to a reduced size and number of PVN oxytocin neurons (91).…”

Sirt 1 activator inhibits the AGE-induced apoptosis and p53 acetylation in human vascular endothelial cells

“…Given the strong anti-apoptosis effect of RSV in the AGE-BSA-treated endothelial cells, our results suggest RSV may be used an alternative therapy for the apoptosis-associated complications in type 2 diabetes, since such complications as diabetic retinopathy (Jiang et al, 2015), cardiomyopathy (Plante et al, 2015) and diabetic nephropathy (Hua et al, 2015). In addition, it is postulated that RSV over-expression positively regulates the insulin secretion and increases the sensitivity of endothelial cells to AGEs.…”