Skeletal glucocorticoid signaling determines aging-related leptin resistance and obesity

Aging contributes to many chronic conditions, including central obesity, insulin resistance and osteoporosis, which are also critical features of glucocorticoid excess. To investigate tissue-specific sites of glucocorticoid (GC) action during aging, we disrupted GC signalling in mouse osteoblasts via transgenic overexpression of the GC-inactivating enzyme, 11β-hydroxysteroid-dehydrogenase type 2 (11β-HSD2). Wild-type mice with intact osteoblastic GC signalling developed leptin resistance, obesity and insulin resistance with aging. In contrast, transgenic (HSD2OB-tg) mice remained lean and leptin-sensitive, and were protected against aging-related hyperinsulinaemia, blunted sympathetic responses and loss of thermogenic adipose tissue. These salutary effects were independent of the osteoblast-derived factors osteocalcin and lipocalin-2. Gene expression analysis of bones from HSD2OB-tg mice indicated an early induction of pro-osteogenic and anti-adipogenic factors, and activation of a local pro-inflammatory TLR4-ZBTB16-NR1H3 network in osteoblastic cells. These findings reveal a critical role for skeletal glucocorticoid signaling in central leptin action, and in impaired metabolic function with aging Wild-type and HSD2^OB-tg mice were housed under standard laboratory conditions at 24°C on a 12:12 h light–dark cycle with free access to standard chow and water. Mice were sacrificed at 3, 6, 12 and 18 m of age for females and 3 and 18 m of age for males. Food intake was determined every 4 to 6 wks. Total RNA extracted from tibiae and femur of 3, 6, 12, and 18 months old WT vs HSD2^ob-tg mice were interrogated using Affymetrix Mouse GeneChip Gene 2.1 ST arrays. Biological triplicates were investigated.