Iron deficiency anemia is associated with lower plasma thyroid hormone concentrations in rodents and, in some studies, in humans. The objective of this project was to determine if plasma triiodothyronine (T3) and thyroxine (T4) kinetics were affected by iron deficiency. Studies were done at a near-thermoneutral temperature (30 degrees C), and a cool environmental temperature (15 degrees C), to determine plasma T3 and T4 kinetics as a function of dietary iron intake and environmental need for the hormones. Weanling male Sprague-Dawley rats were fed either a low Fe diet [iron-deficient group (ID), <5 microg/g Fe] or a control diet [control group (CN), 35 microg/g Fe] at each temperature for 7 wk before the tracer kinetic studies. An additional ID group receiving exogenous thyroid hormone replacement was also used at the cooler temperature. For T4, the disposal rate was >60% lower (89 +/- 6 vs. 256 +/- 53 pmol/h, P < 0.001) in ID rats than in controls at 30 degrees C, and approximately 40% lower (192 +/- 27 vs. 372 +/- 26 pmol/h, P < 0.01) in ID rats at 15 degrees C. Exogenous T4 replacement in a cohort of ID rats at 15 degrees C normalized the T4 concentration and the disposal rate. For T3, the disposal rate was significantly lower in ID rats in a cool environment (92 +/- 11 vs. 129 +/- 11 pmol/h, P < 0.01); thyroxine replacement again normalized the T3 disposal rate (126 +/- 12 pmol/h). Neither liver nor brown fat thyroxine 5'-deiodinase activities were sufficiently different to explain the lower T3 disposal rates in iron deficiency. Thus, plasma thyroid hormone kinetics in iron deficiency anemia are corrected by simply providing more thyroxine. This suggests a central regulatory defect as the primary lesion and not peripheral alterations.

The impact of varying severities of iron-deficiency anemia on fasting blood glucose, plasma triiodothyronine, heart norepinephrine concentrations and resting oxygen consumption were evaluated. Male weanling Sprague-Dawley rats were assigned to one of six dietary groups (4, 6, 11, 16, 23 or 40 mg Fe/kg diet) for 6 wk. Hemoglobin, liver iron and transferrin saturation were significantly lower in the 4 and 6 mg Fe/kg diet groups relative to the other groups and were indicative of anemia, low tissue iron stores and impaired erythropoiesis. Fasting blood glucose and heart norepinephrine concentrations were significantly higher and lower, respectively, in the 4 and 6 mg Fe/kg diet groups than the three highest dietary Fe groups. Although fasting blood glucose was significantly inversely correlated (r = -0.89, P = 0.0001) with hemoglobin concentration; a significant quadratic relationship (R 2 = 0.70, P = 0.0001) existed between hemoglobin and heart norepinephrine concentration. Differences in plasma triiodothyronine concentrations and resting oxygen consumption were not significant among the groups. Thus, base on hemoglobin concentration as an index of the severity of iron deficiency, these findings demonstrate that certain physiological manifestations of iron deficiency occur at even moderate-to-mild degrees of anemia.

Poor temperature regulation in both human and animal models has been associated with iron deficiency anemia. The review examines the evidence for causality in both animals and humans, as well as provides an overview of temperature regulation in homeotherms. A number of investigations conclude that anemia is a central component of the inability of iron-deficient individuals to temperature regulate when they are cold stressed. This is apparently due to effects both on heat production and heat loss rates. The former is related to poor thyroid function in iron deficiency and the latter to the competing demands for tissue oxygenation vs. decreased flood flow to minimize heat losses to the environment. Future research needs are outlined that require integration of endocrinology, physiology, and nutrition disciplines.

To determine if the previously observed alterations in norepinephrine (NE) metabolism and resting metabolic rate in iron-deficient (ID) rats result from hypothyroidism, exogenous thyroxine (T4) and 3,5,3'-triiodothyronine (T3) were administered to ID rats in doses sufficient to normalize the plasma concentrations of these hormones, whereas other ID and control (CN) rats received placebo treatment. Resting oxygen consumption was approximately 25% higher in ID than CN rats; T4 but not T3 treatment alleviated this elevated oxygen uptake. The NE content of interscapular brown adipose tissue (IBAT), liver, and heart was 70-80% lower in ID than CN rats, and NE turnover in the same tissues was likewise 40-60% lower in ID than CN rats, with no systematic effect of either T3 or T4 treatment. Liver T(4)5'-deiodinase activity was 70% lower in ID than CN rats and increased with T4 but not T3 treatment. These experiments show that iron deficiency alters NE and energy metabolism in a way that is mostly independent of its effects on thyroid hormone metabolism.

Poor growth in iron deficiency is commonly observed in animal studies. Previous studies from our laboratory showed that iron-deficient rats are metabolically inefficient and have less body fat than controls and proposed that iron deficiency was related to increased metabolic rates and heat loss. To examine these points more completely, we examined growth and metabolic rate of iron-deficient rats at two environmental temperatures, 25 degrees C and 32 degrees C, and feed efficiency in separate groups of rats during a period of rapid growth. Iron deficiency (hemoglobin [Hb] approximately 60 g/liter) was associated with a systematic elevation of metabolic rate over the 24-hr day with animals at 25 degrees C. This did not occur in animals living in thermoneutrality. Iron deficiency affected growth of animals at 25 degrees C but not at 32 degrees C. Feed efficiency (kcal retained/kcal absorbed) was 25 +/- 4.2 and 31 +/- 4.9 kcal (P < 0.0001), respectively, in iron deficient rats and animals were not anorexic. Use of food-restricted animals allowed the direct calculation that iron deficiency was associated with a 10%-15% increase requirement for growth. We conclude that iron deficiency anemia is associated with a poor feed efficiency and that it is attenuated when nonshivering thermogenesis is minimized by a thermoneutral environment.