This RC1 application, Effect of Perinatal Diet on Developmental Programming of the Skeleton, addresses broad Challenge Area (15) Translational Science, and specific Challenge Topic 15-AR-104 Bone and the Nervous System. This proposal is also directly relevant to Challenge Topic 15-AR-105 Bone and Adipose Tissue. Osteoporosis and obesity are growing sources of morbidity and mortality in the US, and together impose healthcare costs of nearly $100 billion/yr. Fifty percent of women and 20% of men over age 50 are predicted suffer a fracture due to osteoporosis. Moreover 30% of adults in the US are obese and another 30% overweight, with childhood obesity rising at an alarming rate as well. Although the Surgeon General's Report on Bone Health and Osteoporosis stressed the need for good nutrition to maximize bone acquisition during skeletal growth, little is known about how perinatal or postnatal dietary factors impact skeletal acquisition. The discovery of complex interactions between the environment, the brain, adipose tissue, and the skeleton raises the provocative possibility that diseases such as osteoporosis and obesity may share common etiology, and that their origins may lie in childhood. Previous studies have demonstrated that nutrition in early life, including maternal diet during gestation and lactation, can trigger developmental programming that increases the risk of many metabolic diseases, including obesity and type II diabetes, but potential skeletal effects are unknown. Our overall goal is to understand the effect of diet on skeletal acquisition, in particular whether perinatal diet initiates developmental programming of the skeleton that alters postnatal acquisition of bone mass, microarchitecture and strength. Perinatal diet is of particular interest because maternal caloric restriction (CR) and high fat (HF) diet have each been shown to trigger developmental programming that increases the risk of metabolic disease, including obesity and type II diabetes. However, it is unknown whether the skeleton undergoes similar developmental programming that might alter bone mass acquisition and/or the skeletal response to postnatal diet. Our preliminary studies in mice indicate that maternal HF and CR diet influence skeletal acquisition even after pups are weaned onto a normal diet. Several factors may underlie the effects of maternal diet on skeletal acquisition, but most compelling is the observation that prenatal diet alters the perinatal leptin surge, which establishes the sensitivity of hypothalamic neurons to postnatal leptin. We hypothesize that the skeleton undergoes perinatal developmental programming, induced by early life diet that alters postnatal skeletal acquisition and therefore adult bone mass and strength. In particular, we propose that such programming resets the central balance between energy availability and bone mass, and is mediated in part by ss-adrenergic signaling. To test this hypothesis and establish the contribution of developmental programming to skeletal acquisition, and to test the role of hypothalamic control of this process via ss-adrenergic activation, pregnant wildtype (WT) and ss-adrenergic2 receptor knockout (ssAR2-KO) mice will be fed either a normal, HF or CR diet during the last week of gestation and throughout lactation, and pups weaned onto a normal diet. Further, to determine whether perinatal diet initiates developmental programming that alters the skeletal response to postnatal dietary perturbation, WT and ssAR2-KO mice will be weaned either onto the same diet as their mothers were fed, or onto the opposite diet (e.g., prenatal CR weaned to postnatal HF). Mice will be sacrificed at weaning (3 wks of age), adolescence (6 wks of age), young adulthood (12 wks of age) or older adulthood (20 wks of age). Bone mineral density and body composition will be measured in vivo using peripheral dual-energy X-ray absorptiometry;cortical and trabecular bone microarchitecture by microCT;bone strength by biomechanical testing;serum adipokines (leptin, adiponectin), IGF-1 and markers of bone turnover (osteocalcin, TRACP5b, sCTx) by ELISA;and static and dynamic indices of bone formation/resorption, marrow adiposity and cellularity by histomorphometry. These results will provide novel data about relationships among perinatal diet, bone acquisition, and marrow fat during skeletal growth, and may identify perinatal diet as a modifiable risk factor for adult bone disease and thereby change the paradigm by which we view the perinatal environment and skeletal health. Osteoporosis and obesity are growing sources of morbidity and mortality in the US that may have their origins early in development. This project will test the effects of maternal calorie restriction and high fat diet on acquisition of bone mass, microarchitecture and strength in mice. Establishing that maternal / perinatal diet influences peak bone mass acquisition may point to diet as a modifiable risk factor for adult bone disease.