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      Effects of Estradiol on Acute and Recurrent Insulin-Induced Hypoglycemia-Associated Patterns of Arcuate Neuropeptide Y, Proopiomelanocortin, and Cocaine- and Amphetamine-Related Transcript Gene Expression in the Ovariectomized Rat

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          The ovarian steroid hormone, estradiol, is one of several peripheral metabolic signal modulators that are integrated at the level of the arcuate nucleus of the hypothalamus (ARH), and is implicated in the control of ARH neuropeptides that maintain energy balance, including neuropeptide Y (NPY) and proopiomelanocortin (POMC). The present studies utilized quantitative real-time RT-PCR techniques to examine the hypothesis that estradiol regulates ARH NPY, POMC, and cocaine- and amphetamine-related transcript (CART) gene expression during acute insulin-induced hypoglycemia (IIH) and that adaptive modifications in transcriptional reactivity during recurring exposure are steroid dependent. ARH tissue was obtained by micropunch dissection from estradiol benzoate- and oil-implanted ovariectomized (OVX) rats that were treated by subcutaneous injection of one or four doses of the intermediate insulin formulation, Humulin NPH, over as many days, or vehicle alone. Our data show that in OVX plus estradiol benzoate and OVX plus oil groups, a single injection of insulin did not modify gene expression profiles, with the exception of acute hypoglycemic reduction of ARH NPY transcripts in the presence of estrogen. Prior exposure to daily hypoglycemia significantly diminished basal NPY and POMC mRNA levels in estradiol benzoate-, but not oil-implanted OVX rats, but elevated baseline CART transcripts in oil-treated animals. Recurring IIH enhanced ARH NPY gene expression relative to baseline, irrespective of the estradiol manipulation, but net tissue levels were greater in the absence of estrogen. In contrast, reexposure to hypoglycemia decreased POMC and CART gene transcription in estradiol benzoate- and oil-implanted OVX animals, respectively, relative to the single-dose groups. These studies show that estrogen modulates the impact of precedent exposure to IIH on basal and/or hypoglycemia-associated patterns of expression of ARH neuropeptide genes of characterized significance for energy homeostasis. The novel evidence for transcriptional acclimation of NPY, POMC, and CART to recurring IIH supports the possibility that adaptation of compensatory behavioral and physiological responses to acute versus chronic exposure to this metabolic stress may reflect neural regulatory mechanisms involving one or more neurotransmitters encoded by these genes.

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          Most cited references 20

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          Diverse causes of hypoglycemia-associated autonomic failure in diabetes.

           P Cryer (2004)
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            Estrogen blunts neuroendocrine and metabolic responses to hypoglycemia.

            This study tested the hypothesis that estrogen is the mechanism responsible for the sexual dimorphism present in the neuroendocrine and metabolic responses to hypoglycemia. Postmenopausal women receiving (E2; n = 8) or not receiving (NO E2; n = 9) estrogen replacement were compared with age- and BMI-matched male subjects (n = 8) during a single-step 2-h hyperinsulinemic-hypoglycemic clamp. Plasma insulin (599 +/- 28 pmol/l) and glucose (2.9 +/- 0.03 mmol/l) levels were similar among all groups during the glucose clamp. In response to hypoglycemia, epinephrine (2.8 +/- 0.6 vs. 5.8 +/- 0.8 and 4.4 +/- 0.5 nmol/l), glucagon (57 +/- 8 vs. 77 +/- 8 and 126 +/- 18 ng/l), and endogenous glucose production (2 +/- 2 vs. 10 +/- 2 and 6 +/- 3 micro mol x kg(-1) x min(-1)) were significantly lower in E2 vs. both NO E2 and male subjects (P < 0.05). These reduced counterregulatory responses resulted in significantly greater glucose infusion rates (16 +/- 2 vs. 6 +/- 2 and 6 +/- 3 micro mol x kg(-1) x min(-1); P < 0.01) in E2 vs. both NO E2 and male subjects. Pancreatic polypeptide was significantly lower (P < 0.05) in both the E2 and NO E2 groups compared with the male subjects (136 +/- 20 and 136 +/- 23 vs. 194 +/- 16 pmol/l). Last, glycerol (36 +/- 3 vs. 47 +/- 5 micro mol/l; P < 0.05), lactate (1.4 +/- 0.1 vs. 1.8 +/- 0.2 mmol/l; P < 0.05), and muscle sympathetic nerve activity (19 +/- 4 to 27 +/- 4 vs. 27 +/- 5 to 42 +/- 6 bursts/min; P < 0.05) responses to hypoglycemia were all significantly lower in E2 vs. NO E2 subjects. We conclude that estrogen appears to play a major role in the sexual dimorphism present in counterregulatory responses to hypoglycemia in healthy humans.
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              Role of melanocortins in the central control of feeding.

              The injection of a melanocortin peptide or of melanocortin peptide analogues into the cerebrospinal fluid or into the ventromedial hypothalamus in nanomolar or subnanomolar doses induces a long-lasting inhibition of food intake. The effect keeps significant for up to 9 h and has been observed in all animal species so far tested, the most susceptible being the rabbit. The anorectic effect of these peptides is a primary one, not secondary to the shift towards other components of the complex melanocortin-induced behavioral syndrome, in particular grooming. The site of action is in the brain, and the effect is not adrenal-mediated because it is fully exhibited also by adrenalectomized animals. It is a very strong effect, because the degree of feeding inhibition is not reduced in conditions of hunger, either induced by 24 h starvation, or by insulin-induced hypoglycemia, or by stimulation of gamma-aminobutyric acid (GABA), noradrenergic or opioid systems. The microstructural analysis of feeding behavior suggests that melanocortins act as satiety-inducing agents, because they do not significantly modify the latencies to start eating, but shorten the latencies to stop eating. The mechanism of action involves the activation of melanocortin MC(4) receptors, because selective melanocortin MC(4) receptor antagonists inhibit the anorectic effect of melanocortins, while inducing per se a strong stimulation of food intake and a significant increase in body weight. Melanocortins seem to play an important role in stress-induced anorexia, because such condition, in rats, is significantly attenuated by the blockage of melanocortin MC(4) receptors; such a role is not secondary to an increased release of corticotropin-releasing factor (CRF), because, on the other hand, the CRF-induced anorexia is not affected at all by the blockage of melanocortin MC(4) receptors. The physiological meaning of the feeding inhibitory effect of melanocortins, and, by consequence, the physiological role of melanocortins in the complex machinery responsible for body weight homeostasis, is testified by the hyperphagia/obesity syndromes caused by mutations in the pro-opiomelanocortin (POMC) gene, or in the melanocortin MC(4) receptor gene, or in the agouti locus. Finally, recent evidences suggest that melanocortins could be involved in mediating the effects of leptin, and in controlling the expression of neuropeptide Y (NPY).

                Author and article information

                S. Karger AG
                November 2007
                09 October 2007
                : 86
                : 4
                : 270-276
                Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, La., USA
                109678 Neuroendocrinology 2007;86:270–276
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 1, References: 29, Pages: 7
                Appetite and Energy Balance


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