International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity最新文献

Obesity is a major feature in women with polycystic ovary syndrome (PCOS), and evidence suggests that obesity contributes to the pathogenesis of PCOS by aggravating the intrinsic insulin resistance of these women. Hyperinsulinemia appears to increase circulating androgens in PCOS by stimulating ovarian androgen production and suppressing serum SHBG, and also appears to play a pathogenic role in the anovulation of the disorder. The use of insulin sensitizing drugs has been shown to decrease serum insulin in both obese and nonobese women with PCOS, and to simultaneously reduce circulating ovarian androgens and to improve ovulation.

In many species prolactin is of biological importance and has a major role in determining the deposition and mobilization of fat. In human physiology, outside pregnancy, prolactin secretion is altered by increasing body weight in both children and adults. Prolactin in this circumstance appears to be marker of hypothalamic-pituitary function: the prolactin response to insulin-hypoglycaemia, thyrotrophin releasing hormone stimulation and other stimulatory factors may be diminished. In addition, obesity alters the 24h spontaneous release of prolactin with a generalised dampening of release. A number of explanations have been given as possible causes for these alterations, but it seems likely that they reflect obesity per se and are associated with hyperinsulinaemia. Weight reduction, with accompanying decrease in plasma insulin levels, leads to a normalization of prolactin responses in most, but not all, circumstances. To date, no molecular basis has been identified which links prolactin with increasing body fatness, weight and appetite: new data suggests a possible link in obese men between fasting plasma prolactin and leptin concentrations.

Recently, the genes of components of the renin-angiotensin system (RAS), namely angiotensinogen (AGT), angiotensin converting enzyme and angiotensin II receptor have been described in adipose tissue. In animal models the angiotensinogen in adipose tissue has been implicated in the pathogenesis of metabolic alterations and hypertension associated with obesity. The aim of our study was to evaluate the AGT gene expression both in visceral and subcutaneous adipose tissue in obese patients and lean subjects. AGT mRNA levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR) using specific primers. AGT mRNA was expressed at variable levels in obese patients. It was significantly greater in visceral than in subcutaneous adipose tissue. Positive and significant correlation was found between the expression of AGT in visceral adipose tissue and BMI. These data suggest that angiotensinogen may be determinant of fat distribution and may be involved in the plurimetabolic syndrome of central obesity.

Twenty-four-day old female rats were injected with 25 microg recombinant leptin twice daily for 24, 48, 72, or 93 h. Periovarian fat contained significantly greater amounts of aromatase mRNA at 72 and 93 h and estradiol at 72 h after leptin treatment as compared to the ovary. On the other hand, there was an increase in testosterone at 72 h and progesterone at 72 and 93 h after leptin in the ovary as compared to periovarian fat. Cholesterol side chain cleavage and 17alpha-hydroxylase mRNA were found only in the ovary and not periovarian fat. Thus, periovarian fat has a greater capacity to synthesize estrogen than the ovary in the immature rat and adipose tissue may serve as the primary source of estrogen in the prepubertal period which results in the onset of puberty.

GH secretagogues (GHS) act on specific receptors at the pituitary and hypothalamic level and possess potent GH-releasing activity but also stimulate prolactin (PRL), ACTH and cortisol (F) secretion. However, hyperactivity of the HPA axis in obesity has been reported. The objective of this study was to clarify the endocrine activity of GHS in obesity. In nine obese patients (obese OB), 9 F, age, (34.8 +/- 3.7 y, body mass index (BMI), 35.0 +/- 2.2 kg/m2; WHR, 0.9 +/- 0.02), 14 controls (normal subjects, NS), 14 F, 30.4 +/- 0.9 y, 20.0 +/- 0.4 kg/m2), we studied the ACTH, F and GH responses to hexarelin (HEX, 2.0 microg/kg), a peptidyl GHS, alone and preceded by alprazolam (ALP, 0.02 mg/kg), and a benzodiazepine which has an inhibitory effect on corticotroph secretion. The HEX-induced ACTH response in OB was higher than that in n.s., but this difference did not attain statistical significance. In n.s. the HEX-induced ACTH response was abolished by ALP (P < 0.03) which, however, only blunted that in OB (P < 0.02). The GH response to HEX in OB was lower (P < 0.02) than that in n.s.. ALP blunted the GH response to HEX in n.s. (P < 0.03) while it did not modify that in OB. The GABAergic activation by alprazolam abolishes the ACTH response to hexarelin in normal subjects, while it only blunts that in obese subjects. Moreover, alprazolam blunts the GH response to hexarelin in normal but not in obese subjects. Thus, obese patients show partial refractoriness to the inhibitory effect of alprazolam on both corticotroph and somatotroph function.

Leptin in relation to body fat and hormonal regulation of body fat distribution will be treated. Leptin circulating levels are strongly related to the percentage of body fat and in women leptin values are always twofold those observed in men. A role of androgens has been suggested to explain this gender difference. Insulin resistance may contribute to the wide variation in leptin levels. Leptin levels and insulin resistance are increased at the end of pregnancy and normalize after delivery. Furthermore, insulin resistance is associated with elevated plasma leptin levels independent of body fat mass and leptin levels are significantly related to insulin sensitivity independent of BMI. Energy restriction can strongly influence leptin levels, overcoming the effects of body composition changes. The shift from a state of triglycerides storage to a state of release could down-regulate leptin production. Triglyceride flux at the intra-abdominal level depends on the balance between insulin and corticosteroids, which have liposynthetic activity, and between sexual and growth hormones, which have lipolytic activity. Both hormonal and body composition change with ageing, primarily due to a decrease in lipolytic activity, with consequent prevalence of liposynthesis and visceral fat accumulation. Enlargement of intra-abdominal adipose cells is more gradual in men and more abrupt in women after menopause.

Increased basal plasma FFA and lactate concentrations are often present in obesity and may deeply affect insulin action. The inhibition of glucose transport or phosphorylation is thought to be involved in this phenomenon, but the molecular mechanisms on the basis are still unknown. In our laboratory we observed that a chronic infusion of Intralipid plus heparin in rats significantly decreased the insulin dependent-glucose uptake, as well as GLUT4 gene expression in muscular tissue. On the other hand it has been shown that an enhanced plasma lactate concentration may increase insulin secretion and hepatic insulin clearance. Moreover we observed that chronic hyperlactatemia in rats is able to decrease glucose uptake in muscles, while reducing GLUT4 mRNA and protein in the same tissues. In obesity, lactate and FFA overproduction from visceral fat may therefore play a synergic role in reducing insulin sensitivity.

An increased prevalence and incidence of cardiovascular disease is the most important clinical consequence of abdominal obesity. Although defects in glucose handling in skeletal muscle have been extensively investigated, they have failed to clarify why insulin resistance is linked to vascular disease. Non-classic actions of insulin such as those on haemodynamics, nerve function and haemostasis and on lipoprotein metabolism would appear of greater interest in this respect. It is now clear that obese individuals exhibit resistance to some of the non-classic effects of insulin. These include resistance to insulin action on large vessel compliance, nitric oxide-dependent stimulation of vasodilation in resistance vessels, activation of the sympathetic nervous system by insulin but not other stimuli, platelet anti-aggregation and suppression of hepatic very low density lipoprotein production. The exact cause(s) of resistance to these non-classic insulin actions are unclear but their understanding would seem important to understand the links between obesity and cardiovascular disease.