This study describes the previously uncharacterized ontogeny and regulation of truncal adipose reserves in the profoundly GH-deficient dwarf (dw/dw) rat. We show that, despite normal proportionate food intake, dw/dw rats develop abdominal leanness and hypoleptinemia (circulating leptin halved in dw/dw males, P Ͻ 0.05) during puberty. This contrasts with the hyperleptinemia seen in moderately GH-deficient Tgr rats (circulating leptin doubled at 6 wk of age, P Ͻ 0.05) and in GH receptor-binding protein (GHR/BP)-null mice (circulating leptin doubled; P Ͻ 0.05). This lean/hypoleptinemic phenotype was not completely normalized by GH treatment, but dw/dw rats developed abdominal obesity in response to neonatal MSG treatment or maintenance on a high-fat diet. Unlike Tgr rats, dw/dw rats did not become obese with age; plasma leptin levels and fat pad weights became similar to those in wild-type rats. In contrast with truncal leanness, tibial marrow adiposity was normal in male and doubled in female dwarves (P Ͻ 0.01), this increase being attributable to increased adipocyte number (P Ͻ 0.01). Neonatal MSG treatment and high-fat feeding elevated marrow adiposity in dw/dw rats by inducing adipocyte enlargement (P Ͻ 0.05). These results demonstrate that, despite lipolytic influence of GH, severe GH deficiency in dw/dw rats is accompanied by a paradoxical leanness. This lean/hypoleptinemic phenotype is not solely attributable to reduced GH signaling and does not appear to result from a reduction in nutrient intake or the ability of dw/dw adipocytes to accumulate lipid. Disruption of preadipocyte differentiation or adipocyte proliferation in the dw/dw rat may lead to the development of this unusually lean/hypoleptinemic phenotype. adipose tissue; bone marrow fat; leptin; dwarfism IT IS WELL ESTABLISHED that growth hormone (GH) deficiency is usually accompanied by an increase in fat accumulation, whereas conditions of GH excess are normally associated with leanness. However, recent studies have revealed that the relationship between GH status and the degree of adiposity is far from simple. For example, although it is assumed that obesity results from the removal of the lipolytic influence of GH (37), it is also recognized that abdominal obesity results in a secondary reduction in GH secretion (35). Similarly, whereas GH replacement in patients with primary GH deficiency leads to specific depletion of intra-abdominal fat (2, 12), the administration of GH to treat obesity in GH-replete individuals does not elicit a consistent reduction or redistribution in body fat (31). Some of these apparent contradictions may be explained by the depot-specific sensitivity of adipose tissue to the lipolytic action of GH (19). The relationship between GH status and adiposity in rodent models of GH deficiency is similarly complex. In the profoundly GH-deficient lit/lit mouse a significant elevation in total proportionate fat mass (14) is reflected in increased inguinal and retroperitoneal fat, whereas parametrial fat is unaffected (26). In addit...

SUMMARYAntioxidants are known to play an important role in quenching reactive oxygen species (ROS), thus ameliorating oxidative stress. Since increased metabolism associated with exercise can increase oxidative stress, dietary antioxidants may be a limiting factor in determining aspects of physical performance. Here we tested whether oxidative stress associated with flight exercise of captive adult budgerigars, Melopsittacus undulatus differed after they received a diet containing either enhanced (EQ) or reduced levels (RQ) of a nutritional supplement (Nutrivit ® ) rich in antioxidants for 4 weeks. We also assessed differences in take-off escape time, a potential fitness-determining physiological capability. Oxidative stress was measured in two ways: comet assay to measure DNA damage; and analysis of malondialdehyde (MDA), a by-product of lipid peroxidation. Flight exercise appeared to increase oxidative stress. Moreover, birds had a higher percentage of intact DNA (fewer alkali labile sites) in one comet measure and lower levels of MDA after an EQ diet than after an RQ diet. We found no difference in flight performance between the two diets. Our results suggested that birds exerted maximum effort in escape flights, regardless of diet. However, this was at a cost of increased oxidative stress post-flight when on a reduced quality diet, but not when on an enhanced, antioxidant-rich diet. We suggest that dietary antioxidants may prove important in reducing exercise-related costs through multiple physiological pathways. Further work is necessary to fully understand the effects of antioxidants and oxidative stress on exercise performance in the longer term.

Growth hormone (GH)-deficiency is usually associated with elevated adiposity, hyperleptinemia, and increased fracture risk. Since leptin is thought to enhance cortical bone formation, we have investigated the contribution of elevated adiposity and hyperleptinemia on femoral strength in rodent models of GH deficiency. Quantification of the transpubertal development of femoral strength in the moderately GH-deficient/hyperleptinemic Tgr rat and the profoundly GH-deficient/hypoleptinemic dw/dw rat revealed that the mechanical properties of cortical bone in these two models were similarly compromised, a 25-30% reduction in failure load being entirely due to impairment of geometric variables. In contrast, murine models of partial (GH antagonist transgenic) and complete (GH receptor-null) loss of GH signaling and elevated adiposity showed an impairment of femoral cortical strength proportionate to the reduction of GH signaling. To determine whether impaired femoral strength is exacerbated by obesity/hyperleptinemia, femoral strength was assessed in dw/dw rats following two developmental manipulations that elevate abdominal adiposity and circulating leptin, neonatal monosodium glutamate (MSG) treatment, and maintenance on an elevated fat diet. The additional impairment of femoral strength following MSG treatment is likely to have resulted from a reduction in residual activity of the hypothalamo-pituitary-GH-IGF-I axis, but consumption of elevated dietary fat, which did not reduce circulating IGF-I, failed to exacerbate the compromised femoral strength in dw/dw rats. Taken together, our data indicate that the obesity and hyperleptinemia usually associated with GH deficiency do not exert a significant influence over the strength of cortical bone.

The relationship between the degree of GH deficiency and impaired bone integrity is not simple and may be influenced by related endocrine variables. To test the hypothesis that elevated adiposity and hyperleptinaemia are contributory factors, we quantified femoral trabecular organisation in two models of GH deficiency with divergent degrees of adiposity -the moderately GH-deficient/hyperleptinaemic transgenic growth retarded (Tgr) rat and the profoundly GH-deficient/ hypoleptinaemic dw/dw rat. Trabecular density (bone volume/total volume) and surface were reduced by 16% in dw/dw males, with a more fragmented trabecular lattice. This impairment was more pronounced in Tgr rats, with trabecular number and density further reduced (by an additional 21%) and relative surface (bone surface/bone volume), trabecular convexity (structural modal index) and fragmentation (pattern factor) increased. To establish whether the presence of obesity/hyperleptinaemia exacerbates bone impairment in GH deficiency, trabecular structure was assessed in dw/dw rats following diet-induced obesity (DIO). DIO had minimal effect on trabecular architecture, the increased concavity of trabecular surfaces being the only observable effect. Similarly, infusion of leptin into the tibial bone marrow cavity had no effect on trabecular organisation or tibial growth in wild-type rats. However, while this procedure also failed to affect trabecular architecture or osteoclast number in dw/dw rats, distal osteoblast surface was increased by 23%, marrow adipocyte number and epiphyseal plate width being reduced (by 40 and 5% respectively), without increasing caspase-3 immunoreactivity. These findings suggest that while leptin may directly inhibit adipocyte differentiation and favour osteoblast production, hyperleptinaemia makes only a minimal contribution to the impairment of bone structure in GH deficiency.

Captive breeding programmes are common for many parrot species. We show that in small parrots kept in standard cages with ad libitum food, high weight gain was prevalent and linked with a risk of DNA damage. Such damage could explain the poor health, fertility and survival of many captive parrots.