Bromocriptine treatment at the end of lactation prevents hyperphagia, higher visceral fat and liver triglycerides in early-weaned rats at adulthood.

Non-pharmacological early weaning (NPEW) leads offspring to obesity, higher liver oxidative stress and microsteatosis in adulthood. Pharmacological EW (PEW) by maternal treatment with bromocriptine (BRO) causes obesity in the adult progeny but precludes hepatic injury. To test the hypothesis that BRO prevents the deleterious changes of NPEW, we injected BRO into the pups from the NPEW model in late lactation. Lactating rats were divided into two groups: dams with an adhesive bandage around the body to prevent breastfeeding on the last 3 days of lactation and dams whose pups had free suckling (C). Offspring from both groups were subdivided into two groups: pups treated with BRO (intraperitoneal (i.p.) 4 mg/kg per day) on the last 3 days of lactation (NPEW/BRO and C/BRO) or pups treated with the vehicle (NPEW and C). At PN120, offspring were challenged with a high fat diet (HFD), and food intake was recorded after 30 minutes and 12 hours. Rats were killed at PN120 and PN200. At PN120, adipocyte size was greater in the NPEW group but was normal in the NPEW/BRO group. At PN200, the NPEW group presented hyperphagia, higher adiposity, adipocyte hypertrophy, hyperleptinaemia, glucose intolerance and increased hepatic triglycerides. These parameters were normalized in the NPEW/BRO group. In the feeding test, BRO groups showed lower HFD intake at 30 minutes than did their controls; however, at 12 hours, the NPEW group ate more HFD. The treatment with BRO can preclude some deleterious effects of the NPEW model, which prevented the development of overweight and its comorbidities.

Effects of postnatal bromocriptine injection on thyroid function and prolactinemia of rats at adulthood.

Previously, we demonstrated that maternal prolactin inhibition at the end of lactation, using bromocriptine (BRO), leads to an increase in leptin transfer via milk and induces the adult progeny to present hypothyroidism, leptin resistance and metabolic syndrome (obesity, hyperglycemia, hypertriglyceridemia, lower HDL). To test if these alterations are due to direct BRO action on the pups, in the present study we evaluated the long-term effects of direct injection of BRO (0.1µg/once daily) in male Wistar rats from postnatal (PN) day 1 to 10 (early treatment) or from PN11 to 20 (late treatment) on: food intake, body mass, cardiovascular parameters, hormone profile, hypothalamic leptin signaling, glucose homeostasis and thyroid hormone-dependent proteins. The respective controls were injected with methanol-saline. Offspring were killed at adulthood (PN180). Adult PN1-10 BRO-treated animals had lower food intake, hypoprolactinemia, lower leptin action (lower OBR-b, STAT-3 and SOCS-3 mRNA levels in the arcuate nucleus), lower TRH-TSH-thyroid axis as well as lower thyroid hormone markers. On the other hand, adult animals that were BRO-treated during the PN11-20 period showed hyperphagia, higher blood pressure, higher prolactinemia and OBR-b, higher TRH and plasma T3, hypercorticosteronemia as well as higher Dio2 and UCP1 mRNA expression in the brown adipose tissue. Glucose homeostasis was not changed treatment in either period. Our data show that early and late dopamine overexposure during lactation induces diverse metabolic disturbances later in life, increasing the risk of thyroid dysfunction and, consequently, changes in prolactinemia.

Effects of early and late neonatal bromocriptine treatment on hypothalamic neuropeptides, dopaminergic reward system and behavior of adult rats.

In humans, bromocriptine (BRO) is used as a treatment for many disorders, such as prolactinomas, even during pregnancy and lactation. Previously we demonstrated that maternal BRO treatment at the end of lactation programs offspring for obesity and several endocrine dysfunctions. Here, we studied the long-term effects of direct BRO injection in neonatal Wistar rats on their dopaminergic pathway, anxiety-like behavior and locomotor activity at adulthood. Male pups were either s.c. injected with BRO (0.1µg/once daily) from postnatal day (PN) 1 to 10 or from PN11 to 20. Controls were injected with methanol-saline. Body mass, food intake, neuropeptides, dopamine pathway parameters, anxiety-like behavior and locomotor activity were analyzed. The dopamine pathway was analyzed in the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (DS) at PN180. PN1-10 BRO-treated animals had normal body mass and adiposity but lower food intake and plasma prolactin (PRL). This group had higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) in the VTA, higher dopa decarboxylase (DDc), higher D2R and µu-opioid receptor in the NAc. Concerning behavior in elevated plus maze (EPM), BRO-treated animals displayed more anxiety-like behaviors. PN11-20 BRO-treated showed normal body mass and adiposity but higher food intake and plasma PRL. This group had lower POMC in the ARC, lower TH in the VTA and lower DAT in the NAc. BRO-treated animals showed less anxiety-like behaviors in the EPM. Thus, neonatal BRO injection, depending on the time of treatment, leads to different long-term dysfunctions in the dopaminergic reward system, food intake behavior and anxiety levels, findings that could be partially due to PRL and POMC changes.

Role of vitamin D in adipose tissue in obese rats programmed by early weaning and post diet calcium.

SCOPE: Early weaning (EW) is associated with an impairment of offspring development and leads to overweight and higher 25-hydroxyvitamin D (25(OH)D) levels in adulthood, which can be corrected by calcium supplementation, potentially via vitamin D regulation of adipogenesis. METHODS AND RESULTS: We examined vitamin D status in adipose tissue in EW obese rats, treated with calcium. Dams were separated into: EW- dams were wrapped with a bandage to interrupt lactation (last 3 days), and C- pups with free access to milk. At PN120, EW pups were divided in: EW- standard diet, and EWCa- calcium supplementation (10 g of calcium carbonate/kg of chow). On PN21, EW group has hypocalcemia. On PN180, EW group showed lower intestinal calbidin, higher adiposity, and 25(OH)D. In adipose tissue, Cyp27b1/1alpha-Hydroxylase, C/EBPB, PPAR-γ, IL6, TNF-A, and MCP1 were increased, while VDR and IL10 were decreased. Calcium increased calbidin, VDR and prevented adipose tissue dysfunction. EW group has a long-term effect of vitamin D on adipocyte, contributing to pro-inflammatory status and obesity. CONCLUSION: We propose that in obese rat adipocytes, 1,25(OH)2 D down-regulates VDR, resulting in vitamin D resistance, characterized by higher Cyp27b1/1α-Hydroxylase and adipogenesis. Calcium therapy appears to be an outstanding strategy for weight loss and improving endocrine metabolic disorders that are obesity associated.

Does bromocriptine play a role in decreasing oxidative stress for early weaned programmed obesity?

AIMS: Studies have demonstrated that early weaning can promote metabolic syndrome during adulthood and that obesity increases oxidative stress. Thus, we aimed to evaluate redox status in a pharmacological early weaning rodent model programmed for metabolic syndrome at adulthood. MAIN METHODS: Lactating dams were randomly assigned into 2 groups: the early weaning group (BRO), which was treated intraperitoneally with bromocriptine (1 mg/day) to inhibit prolactin secretion for the last 3 days of lactation, and the control group (C), which received the BRO diluent for the same time period. The offspring were killed at 90 (PN90) and 180 (PN180) days after birth. KEY FINDINGS: Early weaning induced greater visceral adiposity and dyslipidemia. At PN90, the BRO offspring showed glucose intolerance with normoinsulinemia and increased plasma and liver superoxide dismutase, and liver glutathione peroxidase activities, which reduced the liver malondialdehyde but not the increased plasma malondialdehyde levels. However, the BRO offspring showed insulin resistance at PN180 and increased plasma glutathione peroxidase, liver superoxide dismutase, and catalase activities. These changes reduced the plasma and liver malondialdehyde levels, which aided in hepatocyte architecture preservation. Additionally, we observed that sirtuin 1 was overexpressed in the BRO group at PN90, but the increased expression was not maintained through PN180, which suggests unfavorable metabolic conditions in the older offspring. SIGNIFICANCE: Despite the observed obesity and glucose homeostasis dysfunction, our data suggest that the early weaning programming induced by bromocriptine can improve the offspring's redox status and may prevent liver damage during adulthood.