The influence of leptin on trabecular architecture and marrow adiposity in GH-deficient rats

Abstract

The relationship between the degree of GH deficiency and impaired bone integrity is not simple and may be influenced by related endocrine variables. To test the hypothesis that elevated adiposity and hyperleptinaemia are contributory factors, we quantified femoral trabecular organisation in two models of GH deficiency with divergent degrees of adiposity -the moderately GH-deficient/hyperleptinaemic transgenic growth retarded (Tgr) rat and the profoundly GH-deficient/ hypoleptinaemic dw/dw rat. Trabecular density (bone volume/total volume) and surface were reduced by 16% in dw/dw males, with a more fragmented trabecular lattice. This impairment was more pronounced in Tgr rats, with trabecular number and density further reduced (by an additional 21%) and relative surface (bone surface/bone volume), trabecular convexity (structural modal index) and fragmentation (pattern factor) increased. To establish whether the presence of obesity/hyperleptinaemia exacerbates bone impairment in GH deficiency, trabecular structure was assessed in dw/dw rats following diet-induced obesity (DIO). DIO had minimal effect on trabecular architecture, the increased concavity of trabecular surfaces being the only observable effect. Similarly, infusion of leptin into the tibial bone marrow cavity had no effect on trabecular organisation or tibial growth in wild-type rats. However, while this procedure also failed to affect trabecular architecture or osteoclast number in dw/dw rats, distal osteoblast surface was increased by 23%, marrow adipocyte number and epiphyseal plate width being reduced (by 40 and 5% respectively), without increasing caspase-3 immunoreactivity. These findings suggest that while leptin may directly inhibit adipocyte differentiation and favour osteoblast production, hyperleptinaemia makes only a minimal contribution to the impairment of bone structure in GH deficiency.

Daily leptin blunts marrow fat but does not impact bone mass in calorie-restricted mice

“…The inverse relationship of leptin and marrow adiposity may reflect direct as well as indirect mechanisms. Bone marrow adipocytes, osteoblasts and myocytes derive from a common mesenchymal progenitor (Bianco et al 2010; Bianco, et al 2008; Zhou et al 2014), and leptin directly promotes osteoblastogenesis and suppresses adipogenesis, such that hypoleptinemia could both increase marrow adiposity and decrease bone mass (Evans, et al 2011; Muruganandan et al 2009). In addition, there may be crosstalk between leptin, estrogen and the GH-IGF-1 axis, both of which are suppressed in CR in humans and animal models (Devlin et al 2010; Misra and Klibanski 2011; Mobbs, et al 2001).…”

Bone quality is affected by food restriction and by nutrition-induced catch-up growth

“…However, in our study the significant reduction in leptin level during RES was associated with decreased cortical thickness as well as a reduction in trabecular BV/TV and Tb.N. As direct infusion of leptin into the bone was shown to increase osteoblast activity (Evans et al 2011, Turner et al 2013, the increase in leptin levels upon refeeding may be associated with the rapid increase in B-ALP.…”

Effect of peripherally administered leptin antagonist on whole body metabolism and bone microarchitecture and biomechanical properties in the mouse

“…Any disturbance in these tightly regulated processes results in skeletal growth anomalies (49,50). Additionally, GH and IGF-I, which are known modulators of bone growth, have a dramatic effect on the balance of adipose tissue development and maintenance interacting with leptin activity to control bone, adipose, and muscle tissues in a complex system (28). GH not only is the regulator bone elongation but also affects bone remodeling and mineralization, and impairment of bone strength in GH deficiency may also be related to its metabolic effects (63,86).…”