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Carbohydrate is a preferred macronutrient of rats during the early dark phase and associated with an increase in norepinephrine (NE) and neuropeptide Y (NPY) in the paraventricular nucleus (PVN). Macronutrient choice is altered during zinc deficiency (ZD). The relationship between NE activity in the PVN and macronutrient choice during early dark was evaluated in rats fed zinc adequate (ZA) or ZD diet for 14 days. Total caloric intake was similar for ZA and ZD groups (-20 kJ) but ZA rats selected 63 +/- 5% of calories as carbohydrate while ZD rats selected 53 +/- 5% of their calories from protein (p < 0.01). Pair-fed (PF) rats selected 62 +/- 5% of calories as carbohydrate. Noradrenergic activity was lower (p < 0.01) in ZD and PF compared to ZA. The association between increased NE in the PVN at dark onset and selection of carbohydrate is not supported by the present results.

Three-choice macronutrient intake studies indicate that zinc-deficient (Zn-) rats selectively decrease intake of carbohydrate. Because glucoprivic stimuli increase food intake and selection for carbohydrate, the ability of Zn- rats to respond to glucoprivation induced by 2-deoxy-D-glucose (2-DG) was tested. Rats were fed a Zn-adequate (Zn+) or Zn- diet. In part 1, rats were challenged with 0, 250, or 400 mg 2-DG/kg BW (i.p.) after zinc deficiency was established. In part 2, rats received saline or 2-DG while zinc deficiency was being induced and then after deficiency was established. Food intake was increased after injection of 2-DG to Zn+ rats; however, food intake was not higher after 2-DG administration to Zn- rats. A dose-response test for 2-DG further confirmed these results. In part 2, it was found that Zn- rats lose the response to 2-DG administration when zinc deficiency-induced anorexia begins, after 3 days of consuming a zinc-deficient diet. It appears that the ability to sense blood glucose concentrations may be impaired during zinc deficiency, and this impairment could be a part of the anorexia that develops during zinc deficiency in the rat.

To determine if alterations in growth hormone releasing factor (GRF) and somatostatin (SRIF) occur during recovery from zinc deficiency and to examine the relationship between these peptides and the increased protein intake observed during zinc repletion, both the hypothalamic release and mRNA levels of GRF and SRIF were measured during zinc deficiency and zinc repletion. Groups of male rats (n = 4-8 each) were provided 3-choice macronutrient diets made either zinc adequate (Zn+) or deficient (Zn-; 30 vs. 1 mg Zn/kg diet). Pair fed, calorie restricted (PF) rats were also maintained. After 28 days, Zn- rats were repleted with Zn+ diets for 2 days and one PF group was allowed free access to the same Zn+ diets for 2 days. Additionally, groups of Zn- and PF rats were repleted 2 days with Zn+ carbohydrate and fat diets but no protein. Hypothalamic GRF and SRIF release was measured in vitro. Basal GRF secretion was not significantly different between Zn-, PF, or Zn+ groups although there was a significant increase (P<0.05) during zinc repletion. PF and Zn- rats repleted 2 days with diets devoid of protein had highest GRF secretion (P<0.01) compared to other groups. There were no differences in GRF mRNA levels among groups. Basal SRIF secretion was significantly lower in Zn- and PF groups compared to Zn+, and SRIF mRNA levels were significantly higher in zinc repleted groups compared to Zn-. These results demonstrate that during zinc repletion, GRF and SRIF secretion and SRIF gene expression are altered concomitantly with protein intake. The present data support involvement of GRF in protein intake changes during zinc repletion.

Growth hormone-releasing factor (GRF) is thought to perform two distinct functions within the brain. GRF synthesized in the median eminence (ME) stimulates the release of growth hormone (GH) from the pituitary, while GRF in the suprachiasmatic nucleus and median preoptic area (SCN/MPOA) may stimulate selection of dietary protein. These two functions may be coupled to regulate and enhance growth. During zinc repletion, a period characterized by increased protein intake and accelerated growth, we examined this coupling by measuring GRF peptide content in hypothalamic sites and neutralizing GRF function by infusing anti-GRF antibody into the hypothalamus during zinc repletion. Total GRF content and GRF content in the ME and SCN/MPOA were decreased in zinc-deficient (Zn-) rats compared to zinc-adequate (Zn+) rats (P < 0.05). There were no differences in GRF content during zinc repletion in either nuclei. Subsequently, we investigated the macronutrient feeding patterns of rats chronically infused with anti-GRF IgG into the lateral ventricle of the brain during zinc repletion. All Zn- and Zn+ rats administered anti-GRF IgG exhibited a reduction in protein intake during zinc repletion. The Zn- rats receiving anti-GRF-IgG consumed equal amounts of total diet compared to those receiving vehicle during the repletion period however they consumed less carbohydrate (P < 0.05) and considerably more fat (P < 0.02). There were no significant differences in carbohydrate or fat intake in Zn+ rats receiving anti-GRF antibody. These results suggest that GRF likely directs protein intake during normal growth, but may interact with additional appetite-controlling neuropeptides during zinc repletion.