Thermoneutrality improves skeletal impairment in adult Prader–Willi syndrome mice

Abstract

Human Prader–Willi syndrome (PWS) is characterised by impairments of multiple systems including the growth hormone (GH) axis and skeletal growth. To address our lack of knowledge of the influence of PWS on skeletal integrity in mice, we have characterised the endocrine and skeletal phenotype of the PWS-IC del mouse model for ‘full’ PWS and determined the impact of thermoneutrality. Tibial length, epiphyseal plate width and marrow adiposity were reduced by 6, 18 and 79% in male PWS-IC del mice, with osteoclast density being unaffected. Similar reductions in femoral length accompanied a 32% reduction in mid-diaphyseal cortical diameter. Distal femoral Tb.N was reduced by 62%, with individual trabeculae being less plate-like and the lattice being more fragmented (Tb.Pf increased by 63%). Cortical strength (ultimate moment) was reduced by 26% as a result of reductions in calcified tissue strength and the geometric contribution. GH and prolactin contents in PWS-IC del pituitaries were reduced in proportion to their smaller pituitary size, with circulating IGF-1 concentration reduced by 37–47%. Conversely, while pituitary luteinising hormone content was halved, circulating gonadotropin concentrations were unaffected. Although longitudinal growth, marrow adiposity and femoral geometry were unaffected by thermoneutrality, strengthened calcified tissue reversed the weakened cortex of PWS-IC del femora. While underactivity of the GH axis may be due to loss of Snord116 expression and impaired limb bone geometry and strength due to loss of Magel2 expression, comprehensive analysis of skeletal integrity in the single gene deletion models is required. Our data imply that thermoneutrality may ameliorate the elevated fracture risk associated with PWS.

Effects of thermoneutrality on food intake, body weight, and body composition in a Prader‐Willi syndrome mouse model

“…However, body weight gain remained unaffected by TN, and daily food intake relative to body weight was reduced by TN in both genotypes. In Braxton et al [37], TN housing did not further impact the reduction in tibial length or femoral length observed in PWS‐IC del mice versus WT mice at RT but did normalize the reduced biomechanical strength of the femoral cortex observed in RT‐housed PWS‐IC del mice.…”

Dynamic Expression of Imprinted Genes in the Developing and Postnatal Pituitary Gland

“…PWS patients experience growth hormone deficiency (GHD) and postnatal growth retardation [ 31 ]. Evidence from murine models suggests that GHD is caused at least in part by pituitary hypoplasia—pituitary mass is reduced by ~40% in PWS imprinting centre deletion mice, with a concomitant reduction in GH content and circulating IGF1 [ 167 ]. The contribution of individual PWS cluster genes to the clinical phenotype has been intensively studied, employing detailed genetic analysis and murine models of individual gene deletions (recently reviewed in [ 168 , 169 ]).…”

DNA Damage in Prader Willi Syndrome Against Obesity

“…In children with PWS obtained abnormal fat distribution conditions, individuals with PWS have lower visceral adipose tissue than the subcutaneous adipose web; in terms of adipocyte proliferation and differentiation, there is a gene called the needed gene, in research it is said that overexpression of the required gene will inhibit adipogenesis, and downregulation of the gene will promote adipogenesis differentiation. In PWS, there is a condition of loss of expression of the needed gene in adipose tissue, which will cause insensitivity to lipolytic stimulation and accumulation of triglycerides (21,22). In children with PWS, there is a unique metabolic condition with low fasting insulin levels and improved insulin sensitivity.…”