Insulin binding and action on adipocytes from female rats with experimentally induced chronic hyperprolactinemia

doi:10.1016/0303-7207(88)90151-7

Molecular and Cellular Endocrinology

Volume 58, Issues 2–3, August 1988, Pages 167-173

https://doi.org/10.1016/0303-7207(88)90151-7 Get rights and content

Abstract

We studied insulin binding and action in adipocytes from female rats with chronic hyperprolactinemia induced by grafting an anterior pituitary gland under the right kidney capsule. Normal basal insulin plasma levels were detected. An increase in insulin binding due to an increased number of receptors was observed (grafted: 193000 ±13000 (6) receptors/cell vs. controls: 136000 ± 17000 (6) receptors/cell, P < 0.05). No changes in receptor affinity were detected (ED₅₀ grafted: 2.3 × 10⁻⁹ M and ED₅₀ controls: 1.6 × 10⁻⁹ M). The antilipolytic activity of insulin was significantly decreased in adipocytes from rats with hyperprolactinemia, indicating an insulin-resistant state in these animals. These findings suggest that the chronic hyperprolactinemic state can modify receptor and post-receptor insulin events in rat parametrial adipose tissue.

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The antipsychotic drug sulpiride does not affect bodyweight in male rats. Is insulin resistance involved?
2002, European Journal of Pharmacology
Previous studies have shown that prolonged administration of antipsychotic drugs induces obesity in female but not in male rats. To explore the mechanisms involved in this sex-dependent effect, we administered the dopamine antagonist sulpiride (20 mg/kg i.p.) or vehicle (0.1 N HCl) to adult male rats during 21 days and daily assessed bodyweight and food intake. Then, we evaluated the glucose tolerance and the serum levels of insulin, leptin, total testosterone, dehydroepiandrosterone-sulfate (DHEA-S), thyroid hormones and blood lipids. In another experiment, food intake and water intake were assessed after acute injections of sulpiride or vehicle into the perifornical lateral hypothalamus. Lastly, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) in the lateral hypothalamus were assessed by in vivo microdialysis after acute systemic injections of sulpiride and vehicle. Chronic sulpiride administration did not affect bodyweight gain and food intake. However, prolactin levels and the area under the glucose and insulin curves were significantly elevated. Acute sulpiride significantly increased food intake, water intake, DOPAC and HVA levels. The acute effects of sulpiride show that this drug is active at the perifornical lateral hypothalamus, which is a brain area where blockade of dopamine receptors stimulates feeding. However, after prolonged administration, sulpiride did not affect body weight. This lack of effect may be related to the impairment of insulin sensitivity, which may prevent body weight gain, and counteract other effects of sulpiride that promote adiposity such as hyperprolactinemia. These findings noticeably contrast with those observed in sulpiride-treated female rats that appear to display enhanced insulin sensitivity. The changes in insulin sensitivity do not appear related to a decrease in androgenic activity, because testosterone and DHEA-S levels were not affected by sulpiride. However, these results should be considered as preliminary because other relevant endocrine variables such as free testosterone, steroid binding globulin and pituitary gonadotrophin levels were not evaluated. Since the same sex-dependent effect on body weight and food intake in rats has been observed during administration of risperidone, which has a different pharmacological profile than sulpiride, future studies must evaluate other neurotransmitters involved in food intake regulation such as serotonin, noradrenaline and histamine.
Antipsychotic drugs and reproductive hormones relationship to body weight regulation
1999, Pharmacology Biochemistry and Behavior
Excessive body weight gain is an undesirable side effect of prolonged administration of antipsychotic drugs (AP), which affects health and interferes with treatment compliance. It has been suggested that hyperprolactinemia-induced endocrine and metabolic abnormalities, particularly in the gonadal steroids, might be involved in the development of this type of weight gain. To test this hypothesis, reproductive hormones, cortisol, dehydro-epiandrosterone-sulfate (DHEA-S), thyroid hormones, and body weight gain were assessed in 18 patients (9 men, 9 women) with mental disorders receiving AP who had been medication-free for at least 3 months before the study, and in 27 placebo-treated subjects (10 men, 17 women). In women, hormones were evaluated during several phases of the menstrual cycle. A significant weight gain was observed in men but not in women. Under AP administration, women displayed significantly lower serum levels of estradiol and progesterone, whereas in men the levels of free testosterone and DHEA-S were significantly lower than in controls. Hyperprolactinemia was observed in both sexes. The levels of follicle-stimulating hormone in women and luteinizing hormone in men were significantly elevated by treatment, thus suggesting that the functioning of the hypothalamus–pituitary–gonads was preserved. In men, such an endocrine profile resembles that observed in subjects with primary obesity. Women under AP administration were found to be relatively hyperandrogenic because of decreased serum estradiol levels, whereas women with primary obesity are known to display actual increased levels of androgens. These endocrine abnormalities may contribute to the excessive weight gain observed after AP treatment, and these could be the target of novel pharmacological treatments.
Glucose tolerance and serum insulin levels in an animal model of obesity induced by sub-acute or chronic administration of antipsychotic drugs
1999, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1.
  1. To assess the role of insulin in the development of the obesity induced by antipsychotic drugs, a glucose tolerance test was conducted in female rats after 10 or 30 days of sulpiride administration.
- 2.
  2. At day 10, the area under the glucose curve did not differ between sulpiride and vehicle-treated rats, however, the area under the insulin curve was significantly decreased by sulpiride. At day, 30 the insulin response was similar in both groups, but the area under the glucose curve was significantly lower in the sulpiride-treated rats.
- 3.
  3. The results suggest that insulin resistance and hyperinsulinemia are not involved in the development and maintenance of the obesity induced by sulpiride. Contrarily, these findings may be related to an increased insulin sensitivity.
- 4.
  4. The absence of hyperinsulinemia and insulin resistance indicates important differences between primary obesity in humans and rodents and this model of drug-induced excessive weight gain.
Mechanism of the neuroleptic-induced obesity in female rats
1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1.
  1. Obesity is an undesirable side effect of neuroleptics which affects 50% approximately of patients under a program of chronic administration.
- 2.
  2. An animal model of neuroleptic-induced obesity and hyperphagia has been developed in female rats treated chronically with sulpiride (20 mg/Kg/ip. for 21 days). However, it is unknown whether or not the hyperphagia is essential for the development of this type of obesity.
- 3.
  3. Sulpiride or vehicle was administered in two experimental conditions: in the first one, food was available in an amount which was three times the previous individual daily food intake; in the second one, the daily food provision was maintained at the individual daily average before starting the treatments.This way hyperphagia was prevented in half of the groups. Besides the body weight gain measurement in all the groups, the serum levels of estradiol, prolactin, glucose and lipids were assessed in the groups with unrestricted food intake.
- 4.
  4. Food restriction prevented the sulpiride-induced weight gain, even though the rats displayed a permanent diestrus which suggests an hyperprolactinemia-induced impairment in the balance of the reproductive hormones that may promote weight gain. However, the basal levels of estradiol were not affected by sulpiride.
- 5.
  5. The high density cholesterol was significantly increased by sulpiride, and the serum glucose levels were significantly decreased, however these changes were only detected during the first week of treatment.
- 6.
  6. The decrease in the serum glucose levels may be an early consequence of hyperinsulinemia.
- 7.
  7. Neuroleptic-induced obesity in rats appears to mimic energy intake, endocrine status and carbohydrate metabolism in humans under chronic neuroleptic administration. However, these rodents did not display the typical changes in blood lipids observed in human obesity.
Influence of prolactin on in vivo and in vitro lipolysis in rabbits
1996, Comparative Biochemistry and Physiology - C Pharmacology Toxicology and Endocrinology
Three experiments were conducted to assess the influence of prolactin on lipolysis in rabbits. In vivo, a single injection of 1 mg of ovine prolactin induces increased plasma glycerol and nonesterified fatty acids concentrations within 30 min (P < 0.01). On the contrary, in vitro, oPRL did not stimulate glycerol release in isolated adipocytes at physiological concentrations (under 10⁻⁸ M). In a third experiment, the effect of chronic hyperprolactinemia on the adrenergic control of lipolysis was studied (daily subcutaneous injections of 1 mg ovine prolactin for 12 days). The weight of perirenal adipose tissue at the end of the period of injections was 27% lower in the prolactin-injected (PRL) rabbits than in the control (CTL) rabbits (88 ± 15 g vs. 120 ± 25 g; P < 0.05). Food intake during the period of injections was 28% lower in the PRL group than in the CTL group (177 ± 21 g/d vs. 246 ± 13g/d; P < 0.05). Basal glycerol release was 157% higher in adipocytes from PRL rabbits than in those from CTL rabbits (P < 0.05). Stimulation of lipolysis with different adrenergic agonists was similar in both groups. These results suggested an indirect influence of prolactin on adipose tissue lipolysis in rabbits, but mechanisms implicated in this effect remain to be elucidated.
Endocrine and psychological evaluation of women with recent weight gain
1995, Psychoneuroendocrinology
A group of 13 consecutive regularly menstruating women who gained at least 5 kg the previous year (Group I) was compared to a control group of similar age, parity, and social class (Group II). The two groups were similar in estimated and observed food intakes; pre- and postprandial gastrin levels; hourly 24-h profiles of cortisol and insulin; urinary cortisol and 17-hydroxycorticosteroids. Group I had higher serum prolactin concentrations at all times than Group II (mean values 14.60 μg/l vs. 8.84 μg/l; p = .0121). Galactorrhea was observed in 5 women from Group I and in none of the women from Group II (p < .05). Group I also differed from Group II in a higher incidence of meaningful life-events the year preceding the study, higher prevalence of sexual dysfunction ( $913$ vs. $413$ ; p < .01) and higher indexes (p < .05) of several parameters in the MMPI and SCL 90. Median serum cortisol and prolactin concentrations were negatively correlated, both in Group I (R = −.669; p = .012) and in the whole sample (R = −.453; p = .0298). It is suggested that the rapid weight gain is part of a neuroendocrine response to environmental stimuli also characterized by hyperprolactinemia. The significant negative correlation between serum prolactin and cortisol indicates that this response differs from, and is possibly an alternative to, the sympathoadrenal “stress” response.

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Insulin binding and action on adipocytes from female rats with experimentally induced chronic hyperprolactinemia

Abstract

Life Sci.

Life Sci.

FEBS Lett.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Am. J. Obstet. Gynecol.

Life Sci.

J. Biol. Chem.

J. Biol. Chem.

Life Sci.

Endocr. Rev.

Endocrinology

Horm. Metab. Res.

IRCS Med. Sci.

Endocrinology

Am. J. Physiol.

Diabetes Res. Clin. Pract.

Biosci. Rep.

Nature

Am. J. Physiol.

Horm. Res.

J. Physiol. (London)

J. Endoerinol.

Neuroendocrinology

Horm. Res.

J. Endoerinol.