Ambient temperature modulates the effects of the Prader-Willi syndrome candidate gene Snord116 on energy homeostasis

Qi, Yue; Purtell, Louise; Fu, Melissa; Sengmany, K.; Loh, Kim; Zhang, L.; Zolotukhin, Sergei; Sainsbury, Amanda; Campbell, Lesley V.; Herzog, Herbert

doi:10.1016/j.npep.2016.10.006

Cited by 20 publications

(19 citation statements)

References 16 publications

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“…Consistent with this, the up-regulated expression of the NPY and pro-opiomelanocortin (POMC) in the hypothalamus under room temperature conditions is one of the likely main drivers of the increased feeding in this model of Snord116 deficiency (12). This is also consistent with the phenotypic study showing that Snord116 specific deletion only in NPY neurones develops the identical metabolic alteration as seen in the germline deletion mice (15). Mechanically, this is likely a result of the disrupted communication between NPY and POMC neurones that control appetite and energy homeostasis regulation (12).…”

supporting

confidence: 88%

“…This is also the area where the major controller of appetite neuropeptide Y (NPY) is located. Considering that NPY expression is strongly influenced by stress, alleviating this stress will reduce NPY levels and, via this mechanism, may help to normalise some of the altered metabolic parameters caused by the Snord116 deletion (15). Consistent with this, the up-regulated expression of the NPY and pro-opiomelanocortin (POMC) in the hypothalamus under room temperature conditions is one of the likely main drivers of the increased feeding in this model of Snord116 deficiency (12).…”

supporting

confidence: 57%

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Hypothalamus Specific Re‐Introduction of SNORD116 into Otherwise Snord116 Deficient Mice Increased Energy Expenditure

Purtell

et al. 2017

J Neuroendocrinology

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The Snord116 gene cluster has been recognised as a critical contributor to the Prader-Willi syndrome (PWS), with mice lacking Snord116 displaying many classical PWS phenotypes, including low postnatal body weight, reduced bone mass and increased food intake. However, these mice do not develop obesity as a result of increased energy expenditure. To understand the physiological function of SNORD116 better and potentially rescue the altered metabolism of Snord116 mice, we used an adeno-associated viral (AAV) approach to reintroduce the product of the Snord116 gene into the hypothalamus in Snord116 mice at different ages. The results obtained show that mid-hypothalamic re-introduction of SNORD116 in 6-week-old Snord116 mice leads to significantly reduced body weight and weight gain, which is associated with elevated energy expenditure. Importantly, when the intervention targets other areas such as the anterior region of the hypothalamus or the reintroduction occurs in older mice, the positive effects on energy expenditure are diminished. These data indicate that the metabolic symptoms of PWS develop gradually and the Snord116 gene plays a critical role during this process. Furthermore, when we investigated the consequences of SNORD116 re-introduction under conditions of thermoneutrality where the mild cold stress influences are avoided, we also observed a significant increase in energy expenditure. In conclusion, the rescue of mid-hypothalamic Snord116 deficiency in young Snord116 germline deletion mice increases energy expenditure, providing fundamental information contributing to potential virus-mediated genetic therapy in PWS.

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supporting

confidence: 88%

supporting

confidence: 57%

Hypothalamus Specific Re‐Introduction of SNORD116 into Otherwise Snord116 Deficient Mice Increased Energy Expenditure

Purtell

et al. 2017

J Neuroendocrinology

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“…In contrast, when housed at thermoneutrality, Ucp1 knockout mice have increased sensitivity to diet-induced obesity (42,43). The fundamental difference in thermoregulation between mice and humans and the growing number of examples that housing temperature influences experimental outcomes (3,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59) argue strongly that thermoneutral housing of mice more accurately reflects the thermal environment in humans and preclinical studies performed in mice should be conducted at housing temperatures that minimize cold stress.…”

Section: Discussionmentioning

confidence: 99%

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

et al. 2020

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Growing female mice housed at room temperature (22 • C) weigh the same but differ in body composition compared to mice housed at thermoneutrality (32 • C). Specifically, mice housed at room temperature have lower levels of white adipose tissue (WAT). Additionally, bone marrow adipose tissue (bMAT) and cancellous bone volume fraction in distal femur metaphysis are lower in room temperature-housed mice. The metabolic changes induced by sub-thermoneutral housing are associated with lower leptin levels in serum and higher levels of Ucp1 gene expression in brown adipose tissue. Although the precise mechanisms mediating adaptation to sub-thermoneutral temperature stress remain to be elucidated, there is evidence that increased sympathetic nervous system activity acting via β-adrenergic receptors plays an important role. We therefore evaluated the effect of the non-specific β-blocker propranolol (primarily β 1 and β 2 antagonist) on body composition, femur microarchitecture, and bMAT in growing female C57BL/6 mice housed at either room temperature or thermoneutral temperature. As anticipated, cancellous bone volume fraction, WAT and bMAT were lower in mice housed at room temperature. Propranolol had small but significant effects on bone microarchitecture (increased trabecular number and decreased trabecular spacing), but did not attenuate premature bone loss induced by room temperature housing. In contrast, propranolol treatment prevented housing temperature-associated differences in WAT and bMAT. To gain additional insight, we evaluated a panel of genes in tibia, using an adipogenesis PCR array. Housing temperature and treatment with propranolol had exclusive as well as shared effects on gene expression. Of particular interest was the finding that room temperature housing reduced, whereas propranolol increased, expression of the gene for acetyl-CoA carboxylase (Acacb), the rate-limiting step for fatty acid synthesis and a key regulator of β-oxidation. Taken together, these findings provide evidence that increased activation of β 1 and/or β 2 receptors contributes to reduced bMAT by regulating adipocyte metabolism, but that this pathway is unlikely to be responsible for premature cancellous bone loss in room temperature-housed mice.

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“…This is remarkable since we have previously shown that this manipulation halved food intake in PWS-IC del mice (Golding et al, 2017). When coupled with evidence that thermoneutrality normalises skeletal length and bone mineral density in Snord116 del mice (Qi et al, 2017), this implies that bone turnover is dramatically reduced at thermoneutrality. This interpretation is supported by evidence that thermoneutrality increases bone formation and reduces bone resorption in growing female C17BL/6J mice, while dramatically reducing food intake and doubling marrow adiposity (Iwaniec et al, 2016).…”

Section: Discussionmentioning

confidence: 83%

Thermoneutrality improves skeletal impairment in adult Prader–Willi syndrome mice

Braxton

Sarpong

Dovey

et al. 2019

Journal of Endocrinology

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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.

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Ambient temperature modulates the effects of the Prader-Willi syndrome candidate gene Snord116 on energy homeostasis

Cited by 20 publications

References 16 publications

Hypothalamus Specific Re‐Introduction of SNORD116 into Otherwise Snord116 Deficient Mice Increased Energy Expenditure

Hypothalamus Specific Re‐Introduction of SNORD116 into Otherwise Snord116 Deficient Mice Increased Energy Expenditure

Effects of Propranolol on Bone, White Adipose Tissue, and Bone Marrow Adipose Tissue in Mice Housed at Room Temperature or Thermoneutral Temperature

Thermoneutrality improves skeletal impairment in adult Prader–Willi syndrome mice

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