Integrative metabolic regulation of peripheral tissue fatty acid oxidation by the SRC kinase family member Fyn.

Mice null for Fyn (a member of the Src family of nonreceptor tyrosine kinases) display a reduced percentage of adipose mass associated with decreased adipocyte cell size. In parallel, there is a substantial reduction in fasting plasma glucose, insulin, triglycerides, and free fatty acids concomitant with decreased intrahepatocellular and intramyocellular lipid accumulation. Importantly, the Fyn null mice exhibit improved glucose tolerance resulting from increased peripheral tissue (adipose and skeletal muscle) insulin sensitivity with a very small effect in the liver. Moreover, whole-body, adipose, and skeletal muscle fatty acid uptake and oxidation are increased along with AMP kinase activation and acetyl-CoA carboxylase inhibition. Together, these data demonstrate crosstalk between Src-family kinase activity and fatty acid oxidation and show that the loss of Fyn markedly improves peripheral tissue insulin sensitivity by relieving a selective negative modulation of AMP kinase activity in adipose tissue and skeletal muscle.

Accretion of bone quantity and quality in the developing mouse skeleton.

UNLABELLED: In this work, we found that bone mineral formation proceeded very rapidly in mice by 1 day of age, where the degree of mineralization, the tissue mineral density, and the mineral crystallinity reached 36%, 51%, and 87% of the adult values, respectively. However, even though significant mineralization had occurred, the elastic modulus of 1-day-old bone was only 14% of its adult value, indicating that the intrinsic stiffening of the bone lags considerably behind the initial mineral formation. INTRODUCTION: To meet the mechanical challenges during early development, the skeleton requires the rapid accretion of bone quality and bone quantity. Here, we describe early bone development in the mouse skeleton and test the hypothesis that specific compositional properties determine the stiffness of the tissue. MATERIALS AND METHODS: Tibias of female BALB mice were harvested at eight time-points (n = 4 each) distributed between 1 and 40 days of age and subjected to morphometric (muCT), chemical (Fourier transform infrared microspectroscopy), and mechanical (nanoindentation) analyses. Tibias of 450-day-old mice served as fully mineralized control specimens. RESULTS: Bone growth proceeded very rapidly; at 1 day of age, the degree of mineralization (phosphate/protein ratio), the density of mineralized bone (TMD), and mineral crystallinity had reached 36%, 51%, and 87% of the adult (450 days) values, respectively. Spatially, the variability in mineralization across the mid-diaphysis was very high for the early time-points and declined over time. In contrast to the notable changes in mineralization, carbonate substitution into the mineral lattice (carbonate/phosphate ratio) and collagen cross-linking did not show any significant changes over this time period. Even though significant mineralization had occurred, the elastic modulus of 1-day-old bone was only 14% of the adult value and increased to 89% (of its adult value) after 40 days. Between samples of different time-points, significant positive correlations were observed between the elastic modulus and TMD (r(2) = 0.84), phosphate/protein ratio (r(2) = 0.59), and crystallinity (r(2) = 0.23), whereas collagen cross-linking showed a small but significant negative correlation (r(2) = 0.15). CONCLUSIONS: These data indicate that specific chemical and morphometric properties modulate bone's stiffness during early growth. The intrinsic stiffening of the bone, however, lags considerably behind the initial mineral formation, emphasizing the importance of bone mineral quality for optimizing matrix integrity.

Low-level mechanical vibrations can influence bone resorption and bone formation in the growing skeleton.

Short durations of extremely small magnitude, high-frequency, mechanical stimuli can promote anabolic activity in the adult skeleton. Here, it is determined if such signals can influence trabecular and cortical formative and resorptive activity in the growing skeleton, if the newly formed bone is of high quality, and if the insertion of rest periods during the loading phase would enhance the efficacy of the mechanical regimen. Eight-week-old female BALB/cByJ mice were divided into four groups, baseline control (n = 8), age-matched control (n = 10), whole-body vibration (WBV) at 45 Hz (0.3 g) for 15 min day(-1) (n = 10), and WBV that were interrupted every second by 10 of rest (WBV-R, n = 10). In vivo strain gaging of two additional mice indicated that the mechanical signal induced strain oscillations of approximately 10 microstrain on the periosteal surface of the proximal tibia. After 3 weeks of WBV, applied for 15 min each day, osteoclastic activity in the trabecular metaphysis and epiphysis of the tibia was 33% and 31% lower (P <0.05) than in age-matched controls. Bone formation rates (BFR.BS(-1)) on the endocortical surface of the metaphysis were 30% greater (P <0.05) in WBV than in age-matched control mice but trabecular and middiaphyseal BFR were not significantly altered. The insertion of rest periods (WBV-R) failed to potentiate the cellular effects. Three weeks of either WBV or WBV-R did not negatively influence body mass, bone length, or chemical bone matrix properties of the tibia. These data indicate that in the growing skeleton, short daily periods of extremely small, high-frequency mechanical signals can inhibit trabecular bone resorption, site specifically attenuate the declining levels of bone formation, and maintain a high level of matrix quality. If WBV prove to be efficacious in the growing human skeleton, they may be able to provide the basis for a non-pharmacological and safe means to increase peak bone mass and, ultimately, reduce the incidence of osteoporosis or stress fractures later in life.

Genetically linked site-specificity of disuse osteoporosis.

UNLABELLED: The genetic influence on bone loss in response to mechanical unloading was investigated within diaphyseal and distal femoral regions in three genetically distinct strains of mice. One mouse strain failed to lose bone after removal of function, whereas osteopenia was evident in multiple regions of the remaining two strains but in different areas of the bone. INTRODUCTION: It is well recognized that susceptibility to osteoporosis is, in large measure, determined by the genome, but whether this influence is systemic or site-specific is not yet known. Here, the extent to which genetic variations influence regional bone loss caused by disuse was studied in the femora of adult female mice from three inbred strains. MATERIALS AND METHODS: Adult C57BL/6J (B6), C3H/HeJ (C3H), and BALB/cByJ (BALB) mice were subjected to 15-21 days of disuse, achieved by hindlimb suspension, and six distinct anatomical regions of the femur were analyzed by high-resolution microCT. RESULTS AND CONCLUSIONS: In B6 mice, the amount of disuse stimulated bone loss was relatively uniform across all regions, with 20% loss of trabecular bone and 10% loss of cortical bone. The degree of bone loss in BALB mice varied greatly, ranging from 59% in the metaphysis to 3% in the proximal diaphysis. In this strain, the nonuniformity of bone loss was directly related to the nonuniform distribution of baseline bone morphology (r2 = 0.94). In direct contrast with BALB and B6, disuse failed to produce significant losses of bone in any of the analyzed regions of the C3H mice. Instead, these animals displayed a unique compensatory mechanism to disuse, where the large loss of calcified tissue from the endocortical surface (-24%) was compensated for by an expansion of the periosteal envelope (10%). These data indicate a strong, yet complex, genetic dependence of the site-specific regulation of bone remodeling in response to a powerful catabolic signal. Consequently, the skeletal region of interest and the genetic make-up of the individual may have to be considered interdependently when considering the pathogenesis of osteoporosis or the efficacy of an intervention to prevent or recover bone loss.