CENTRAL INSULIN ADMINISTRATION REDUCES NEUROPEPTIDE Y mRNA EXPRESSION IN THE ARCUATE NUCLEUS OF FOOD-DEPRIVED LEAN (Fa/Fa) BUT NOT OBESE (fa/fa) ZUCKER RATS

Abstract

By acting in the brain, insulin suppresses food intake, whereas neuropeptide Y (NPY) has the opposite effect. Since fasting increases NPY gene expression in the hypothalamic arcuate nucleus (ARC) and also lowers circulating insulin levels, we hypothesized that the anorexiant effect of insulin could result from insulin inhibition of NPY gene transcription in the ARC. Therefore, we determined whether the administration of insulin (200 mU per 12 hrs) into the 3rd cerebral ventricle of lean (Fa/Fa) female Zucker rats (n = 5) during 48 hrs of food deprivation reduces the expression of preproNPY mRNA in the ARC compared to vehicle-treated controls (n = 5). Coronal sections of rat brain were hybridized with an oligonucleotide probe complementary to preproNPY mRNA and apposed to x-ray film. Hybridization was quantified in both the ARC and the hippocampal dentate gyrus by computerized image analysis of the resulting autoradiographs. Central insulin significantly reduced the area of hybridization in the ARC (0.235 +/- 0.017 mm2; mean +/- SE) compared to vehicle-treated controls (0.331 +/- 0.037 mm2; p less than 0.05), but was without effect in the hippocampus. Thus, insulin reduced the expression of mRNA for NPY specifically in the ARC. Since the genetically obese (fa/fa) Zucker rat is insensitive to the anorexiant effect of insulin and over-expresses NPY in the ARC, we next tested the hypothesis that insulin does not suppress NPY mRNA expression in the ARC of these rats. Consistent with this hypothesis, central insulin administration to obese Zucker rats during 48 hrs of food deprivation (n = 6) did not lower hybridization area in the ARC compared to vehicle alone (n = 4) (0.286 +/- 0.036 vs. 0.248 +/- 0.019 mm2; p greater than 0.05). We conclude that insulin suppresses the expression of mRNA for NPY in the ARC of fasted lean but not obese Zucker rats. Regulation of hypothalamic NPY gene expression by insulin may account for its anorexiant effect, and a defect in this action may contribute to certain forms of obesity.

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

“…Mechanisms to explain the weight gain caused by insulin resistance and hyperinsulinaemia have been attributed to defective insulin signalling in the hypothalamus [4,6,22,23,24,25,26]. However, the intracellular mechanisms involved are largely unknown.…”

Low physical performance in obese adolescent boys with metabolic syndrome

“…24 While in some cases a decreased activity of the sympathetic nervous system is emphasized in the aetiology of obesity, some data suggest that overfeeding and hyperinsulinaemia stimulates the sympathetic nervous system. 25 ± 27 In addition, it has been demonstrated that an increase in brain insulin reduces neuropeptide Y and its gene expression in the arcuate nucleus 28 which results in the stimulation of the sympathetic nervous system. 29 Fripp et al 6 demonstrated a correlation between physical ®tness and risk factors for atherosclerosis in male adolescent population.…”

Blood Glucose Dynamics and Control of Meal Initiation: A Pattern Detection and Recognition Theory

“…This model accounts for the central integration of a circulating signal related to adipose tissue mass, plasma insulin concentration, and the resultant modulation of daily food intake and, thus, body weight regulation. The current formulation of this evolving theory and the experimental evidence supporting it have been reviewed (63,104,105,135). In the brain insulin hypothesis, the 24-h and day-today fluctuation or pattern of plasma insulin concentration, when integrated by brain insulin transport and subsequent insulin-dependent signal transduction, is a critical variable of the control of body weight.…”