Innate immunity is the primary and most ancient defense against infection. Although critical to survival, coordinating protection against a foreign organism is energetically costly, creating the need to reallocate substrates from nonessential functions, such as growth and nutrient storage. However, the mechanism by which infection or inflammation leads to a reduction in energy utilization by these dispensable processes is not well understood. Here, we demonstrate that activation of the Toll signaling pathway selectively in the fat body, the major immune and lipid storage organ of the fruit fly, Drosophila melanogaster, leads to both induction of immunity and reallocation of resources. Toll signaling in the fat body suppresses insulin signaling both within these cells and non-autonomously throughout the organism, leading to a decrease in both nutrient stores and growth. These data suggest that communication between these two regulatory systems evolved as a means to divert energy in times of need from organismal growth to the acute requirement of combating infection.fat body ͉ immunity ͉ Toll ͉ insulin

Adrenal steroids are essential for homeostasis and survival during severe physiological stress. Analysis of a patient heterozygous for the steroidogenic factor-1 (SF-1) gene suggested that reduced expression of this nuclear receptor leads to adrenal failure. We therefore examined SF-1 heterozygous (؉͞؊) mice as a potential model for delineating mechanisms underlying this disease. Here we show that SF-1 ؉͞؊ mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting steroidogenic protein StAR, help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF-1 heterozygotes are revealed under stressful conditions, demonstrating that normal gene dosage of SF-1 is required for mounting an adequate stress response. Our findings predict that natural variations leading to reduced SF-1 function may underlie some forms of subclinical adrenal insufficiency, which become life threatening during traumatic stress. P hysiological adaptation to infection, injury, and starvation requires an endocrine stress response that is mediated by the hypothalamic-pituitary-adrenal (HPA) axis. In instances of adrenal crisis or adrenal insufficiency, the inability to mount an adequate response to acute physiological stress can lead to morbidity (1). In response to stress, adrenal secretion of glucocorticoids is initiated by the hypothalamic neuropeptide corticotropin releasing hormone (CRH), which stimulates pituitary release of adrenocorticotropic hormone (ACTH). Activation of ACTH receptors in the adrenal cortex promotes glucocorticoid synthesis and secretion; glucocorticoids then act on a wide range of target tissues (2). Human diseases associated with an impaired stress response arise from either primary defects in the adrenal or secondary defects at the level of the hypothalamus or pituitary. Primary adrenal insufficiency is most commonly due to bilateral adrenal gland destruction resulting from autoimmune and infectious diseases, such as AIDS and tuberculosis (1). Other forms of primary adrenal insufficiency result from inherited defects in cortisol biosynthesis and manifest as adrenal hyperplasia because of lack of adrenal feedback in the HPA axis (1). Finally, rarer forms of familial adrenal insufficiency are associated with mutations in members of the nuclear receptor superfamily. For example, mutations in the X-linked gene Dax1 lead to abnormal adrenal development resulting in adrenal hypoplasia, as well as hypogonadotropic hypogonadism (3-5).A similar, but less well-characterized form of adrenal insufficiency was revealed by the analysis of a single patient with a heterozygous mutation in the orphan nuclear receptor steroidogenic factor-1 (SF-1). This individual was diagnosed with primary adrenal insufficiency as well as XY sex reversal, suggesting that SF-1 functions in a dose-dependent manner in humans (6). A large number...

The importance of steroidogenic factor-1 (SF-1) gene dosage in endocrine function is evidenced by phenotypes associated with the heterozygous state in mice and humans. Here we examined mechanisms underlying SF-1 haploinsufficiency and found a striking reduction (12-fold) in SF-1 heterozygous (+/-) adrenocortical size at embryonic day (E) 12. Loss of one SF-1 allele led to a selective decrease in adrenal precursors within the adrenogonadal primordium at E10.0, without affecting the number of gonadal precursors, as marked by GATA-4. Beginning at E13.5, increased cell proliferation in SF-1 +/- adrenals allows these organs to approach but not attain a normal size. Remarkably, neural crest-derived adrenomedullary precursors migrated normally in SF-1 +/- and null embryos. However, later in development, medullary growth was compromised in both genotypes. Despite the small adrenal size in SF-1heterozygotes, an unexpected elevation in steroidogenic capacity per cell was observed in primary adult adrenocortical SF-1 +/- cells compared with wild-type cells. Elevated cellular steroid output is consistent with the up-regulation of some SF-1 target genes in SF-1 +/- adrenals and may partially be due to an observed increase in nerve growth factor-induced-B. Our findings underscore the need for full SF-1 gene dosage early in adrenal development, but not in the adult adrenal, where compensatory mechanisms restore near normal function.