Research Article: Insulin suppresses ghrelin-induced calcium signaling in neuropeptide Y neurons of the hypothalamic arcuate nucleus

Date Published: November 8, 2011

Publisher: Impact Journals LLC

Author(s): Yuko Maejima, Daisuke Kohno, Yusaku Iwasaki, Toshihiko Yada.

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Abstract

Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) play an important role in feeding regulation. Plasma levels of ghrelin and insulin show reciprocal dynamics before and after meals. We hypothesized that ghrelin and insulin also exert reciprocal effects on ARC NPY neurons. Cytosolic Ca2+ concentration ([Ca2+]i) was measured by fura-2 microfluorometry in single neurons isolated from ARC of adult rats, followed by immunocytochemical identification of NPY neurons. Ghrelin at 10−10 M increased [Ca2+]i in isolated ARC neurons, and co-administration of insulin concentration-dependently suppressed the ghrelin-induced [Ca2+]i increases. Insulin at 10−16 M, 10−14 M, 10−12 M and 10−10 M counteracted ghrelin action in 26%, 41%, 61% and 53% of ghrelin-responsive neurons, respectively, showing a maximal effect at 10−12 M, the estimated postprandial concentration of insulin in the brain. The majority (>70%) of the ghrelin-activated insulin-inhibited neurons were shown to contain NPY. Double-immunohistochemistry revealed that 85% of NPY neurons in ARC express insulin receptors. These data demonstrate that insulin directly interacts with ARC NPY neurons and counteracts ghrelin action. Our results suggest that postprandial increase in plasma insulin/ghrelin ratio and insulin inhibition of ghrelin action on ARC NPY neurons cooperate to effectively inhibit the neuron activity and terminate feeding.

Partial Text

Ghrelin and insulin are, respectively, orexigenic and anorexigenic hormones regulating feeding behavior [1-3]. Furthermore, insulin and ghrelin regulate energy and glucose metabolism [4, 5]. Insulin and ghrelin are also implicated in learning/memory [6, 7], and insulin action is characteristically related to the Alzheimer disease [7]. All these functions are known to influence aging. In fact, insulin signaling regulates longevity, and ghrelin could promote longevity and serve as an anti-aging hormone [4, 8, 9, 10, 11]. These observations suggest that insulin, ghrelin and their interaction play an important role in regulation of feeding, metabolism and aging.

Insulin plays an important role in the central regulation of feeding and metabolism [3, 16], including its action via the hypothalamus to suppress hepatic glucose production [20]. Insulin enters the brain through the blood-brain barrier (BBB) [21]. However, the target neurons of insulin in the hypothalamus have not been fully clarified. ARC is considered the first order center that senses peripheral signals including hormones. Insulin deficient type 1 diabetes exhibits hyperphagia and is associated with increased expression of NPY in ARC [18]. Furthermore, type 2 diabetic Goto-Kakizaki (GK) rats with impaired insulin secretion and action also show hyperphagia and increased expression of NPY in ARC [22]. Hence, the ARC NPY neuron has been suggested as a candidate target for anorexigenic action of insulin. The present study demonstrated that insulin directly interacts with ARC NPY neurons and counteracts the ghrelin action to increase [Ca2+]i. Since the ghrelin-induced [Ca2+]i increase in ARC NPY neurons is coupled to stimulation of food intake [19], the insulin action to counteract ghrelin in ARC NPY neurons is suggested to be linked to inhibition of feeding. Regarding the insulin antagonism against ghrelin, insulin reportedly decreases preproghrelin mRNA expression in proGhrelin-expressing mHypoE-38 neuronal cell line [23].

 

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