Inhibition of hypothalamic neuropeptide Y gene expression by insulin.

Abstract

Insulin acts in the brain to suppress feeding, whereas neuropeptide Y (NPY) has the opposite effect. Since fasting lowers plasma insulin levels and increases hypothalamic synthesis of NPY, we proposed that insulin may inhibit hypothalamic NPY gene expression. To test this hypothesis, we used RIA and in situ hybridization histochemistry to determine if centrally administered insulin could reduce levels of both NPY and its messenger RNA (mRNA) in discreet hypothalamic regions during fasting. Three groups of Long-Evans rats were entered into a 72-h study protocol. One group was fed ad libitum during this period, while the others were fasted. Fed rats received intracerebroventricular (icv) injections of saline vehicle at 12-h intervals, whereas fasted groups received icv vehicle alone or with insulin (4 mU/12 h). In vehicle-only treated rats, fasting significantly increased expression of preproNPY mRNA in the arcuate nucleus to 179 +/- 20% of fed controls. Administration of icv insulin during fasting abolished this increase (99 +/- 14% of fed controls; P less than 0.05 vs. fasted, vehicle-treated rats). Central insulin administration during fasting also reduced immunoreactive NPY concentrations in samples punched from the paraventricular nucleus (PVN) (875 +/- 122 pg/punch) to levels below vehicle-only treated rats (1396 +/- 435 pg/punch; P less than 0.05), similar to free-feeding control values (814 +/- 170 pg/punch). By comparison, neither fasting nor central insulin administration altered NPY levels in four other hypothalamic regions (supraoptic, ventromedial, dorsomedial, and arcuate nuclei). Continuous icv insulin infusion at a lower dose (2 mU/day) produced a similar result during a shorter period (48 h) of food deprivation in Wistar rats. In this study, central insulin infusion also inhibited the fasting-related increase in arcuate preproNPY mRNA levels and did not affect plasma glucose or insulin levels. This suggests that insulin acts locally to inhibit hypothalamic NPY mRNA expression. We conclude that the increase of levels of NPY in the PVN and preproNPY mRNA in the arcuate nucleus during fasting are inhibited by icv insulin. Fasting, therefore, increases NPY biosynthesis along an arcuate nucleus-PVN pathway in the hypothalamus via a mechanism dependent on low insulin levels.

Identification of targets of leptin action in rat hypothalamus.

“…Since obesity in these animals results from mutation of the leptin receptor (fa/fa) (3), our data suggest that normal leptin receptor function is required for the effect of icv leptin to influence hypothalamic NPY and CRH gene expression. These results are similar to those of previous studies demonstrating that icv administration of insulin lowers arcuate nucleus NPY mRNA levels during fasting in normal rats, but not in obese fa/fa rats (16,28). Insulin and leptin, therefore, both appear to contribute to the regulation of hypothalamic NPY gene expression during fasting.…”

Neuropeptide Y and energy balance: one way ahead for the treatment of obesity?

“…The ARC is very rich in insulin receptors although their precise relationship to the NPY-synthesizing cells is not yet defined [ 1321. Insulin-injected ICV in food-deprived lean rats prevents the rise in NPY mRNA levels which normally occurs in the ARC, but in an interesting parallel with its appetite-suppressing effects, insulin fails to affect NPY mRNA in similarly treated f a / f u Zucker rats [ 142,1431. Insulin may, therefore, enter the hypothalamus from the circulation and inhibit the NPYergic projection from the ARC to the PVN.…”

“…This could readily explain the pathway's increased activity in food deprivation, diabetes, exercise and lactation as circulating insulin levels are substantially reduced in all these conditions. By contrast, the ARC-PVN pathway could be activated in genetically obese rodents because their hypothalamic NPYergic neurones are insensitive to inhibition by insulin, even at the grossly elevated circulating levels which characterize these syndromes [7,103,142].…”

“…Hyperinsulinaemia per se would be anticipated to decrease NPY synthesis in the ARC [142] yet acute (2.5 h) hyperinsulinaemia increased NPY concentrations in the ARC with no other regional changes [ 1461 (Fig. 5).…”

Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

“…Importantly, these 2 populations of neurons have opposing effects on food intake and body weight; the activation of POMC neurons results in reduced food intake and weight loss, whereas the activation of NPY/AgRP neurons results in increased food intake and weight gain. Direct delivery of insulin into the brain increases the expression of anorexigenic peptides α-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and decreases the expression of the orexigenic peptides NPY and AgRP [64,65,66]. Accordingly, central and intranasal delivery of insulin resulted in reduced food intake in rats, baboons, and humans [67,68,69].…”