Obese-diabetic female <i>Ksr2</i> knockout mice develop brittle bones near end of life

The influence of obesity and type 2 diabetes (T2D) on the skeleton is complex, with affected individuals having higher fracture risk despite having higher BMD. To evaluate how obesity and T2D affect skeletal health, we studied mice with disruption of a gene that regulates energy intake and expenditure, <i>Ksr2</i>, which results in reduced metabolic rate and severe insulin resistance in both mice and a subpopulation of humans. Relative to 28-wk-old littermate sibling controls, <i>Ksr2</i> mutants weighed more than double the body and fat weight. Moreover, leptin and insulin were elevated by 20- and 10-fold in <i>Ksr2</i> mutant serum, consistent with prior reports of a T2D state. Micro-computed tomography analysis revealed increased trabecular bone volume (BV) per total volume (TV) in the mutant's distal femur, proximal tibia, and vertebrae. While the bone size (cortical (Ct) cross-sectional bone area) was increased by 7%-11% at the mid-diaphysis of femurs and tibiae, Ct BV adjusted for TV was unaffected. Three-point bending tests revealed increased ultimate force to failure and ultimate bending stress at the mid-diaphysis of femurs by 13% and 8%, respectively in <i>Ksr2</i> mutants. However, bone toughness, a measure of bone quality that assesses how well Ct bone resists fracture, was reduced by 25%. To determine the cause of reduced bone quality in <i>Ksr2</i> mutants, we evaluated femurs for bone hydration by nuclear magnetic resonance relaxometry and found reduced pore water (20%) in <i>Ksr2</i> mutant femurs relative to controls. Moreover, analysis of hydrolysates from femurs for advanced glycation end products revealed a 14% increase in <i>Ksr2</i> mutants. Based on our data, we conclude that while bone density and strength are increased in mice with obesity-induced insulin resistance, bone toughness is compromised due to reduced bone tissue quality, thus suggesting therapeutics focused on improving bone tissue are needed to reduce fracture risk in obese patients.