Pharmacological Inhibition of Inositol Hexakisphosphate Kinase 1 Protects Mice against Obesity-Induced Bone Loss.
Pharmacological Inhibition of Inositol Hexakisphosphate Kinase 1 Protects Mice against Obesity-Induced Bone Loss.
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肥胖和糖尿病对骨骼健康有不利影响，导致骨折风险增加和骨折愈合受损，这些疾病与显著的发病率和死亡率相关，治疗费用高昂。由于抗糖尿病药物对骨骼健康有负面或未知的影响，这限制了它们的有效性，因此控制肥胖引起的骨质流失变得复杂。肌醇六磷酸激酶1 （IP6K1）作为能量消耗的重要调节因子，有数据显示其抑制作用可以保护小鼠免受饮食诱导的肥胖。在本文中，我们表明，即使在热中性条件下，高脂肪饮食喂养后IP6K1的药理抑制也可以保护小鼠免受体重增加及其相关代谢紊乱的影响，并且激酶抑制还可以保护骨量，骨微结构和骨髓中的骨干/祖细胞池。肥胖对男性生育能力也有负面影响，但IP6K1长期抑制对男性生殖参数没有不利影响。这些研究结果表明，由于IP6K1抑制对骨骼的保护作用，IP6K1是血糖控制的首选靶点。肥胖和2型糖尿病（T2DM）是继发性骨质疏松症的重要危险因素，因为高血糖和过多的体脂会对骨代谢产生负面影响。虽然抗糖尿病药物的种类正在扩大，但它们对骨代谢的负面或未知影响限制了其有效性。肌醇己基磷酸激酶1 （IP6K1）的失活通过增加产热能量消耗来保护小鼠免受高脂肪饮食（HFD）诱导的肥胖（DIO）和胰岛素抵抗，但该激酶的作用及其对骨代谢的抑制后果尚不清楚。为了确定肥胖小鼠的IP6K1抑制是否对肥胖诱导的代谢紊乱和骨质丢失提供保护，我们在热中性条件下让2个月大的小鼠保持正常的食物控制饮食或HFD 100 d。从第40天开始，HFD喂养的小鼠分为两组，每天注射载药或pan-IP6K抑制剂TNP [N2-（间三氟苯），N6-（对硝基苯）嘌呤]。饲喂hfd的小鼠出现肥胖、高血糖、高脂血症和继发性骨质疏松症，而TNP可保护小鼠免受hfd诱导的代谢和脂质紊乱，并保留骨量、矿物质密度和小梁微结构，这些与降低血清瘦素水平、减少骨髓脂肪和保存骨髓内骨骼干/祖细胞（SSPCs）相关。TNP还表现出降压活性，这是该药物未实现的益处，并且长期服用对精子发生没有不利影响。综上所述，这些数据表明，使用选择性抑制剂（如TNP）抑制IP6K1，可能提供一种有效的策略来控制肥胖和2型糖尿病，因为它具有保骨作用。
Obesity and diabetes have detrimental impacts on skeletal health that result in an increased fracture risk and impaired fracture healing, conditions associated with significant morbidity and mortality and that are costly to treat. Managing obesity-induced bone loss is complicated by the fact that anti-diabetic drugs have negative or unknown impacts on bone health, which limits their effectiveness. Inositol hexakisphosphate kinase 1 (IP6K1) functions as a prominent regulator of energy expenditure based on data showing its inhibition protects mice from diet-induced obesity. In this paper, we show that the pharmacological inhibition of IP6K1 after the onset of a high-fat diet feeding protects mice against weight gain and its associated metabolic derangements even under thermo-neutral conditions, and that kinase inhibition also preserves bone mass, bone micro-architecture, and the pool of skeletal stem/progenitors in bone marrow. Obesity also has negative impacts on male fertility, but prolonged IP6K1 inhibition had no adverse impacts on male reproductive parameters. These findings identify IP6K1 as a preferred target for glycemic control due to the bone sparing effects of IP6K1 inhibition. Obesity and type II diabetes mellitus (T2DM) are prominent risk factors for secondary osteoporosis due to the negative impacts of hyperglycemia and excessive body fat on bone metabolism. While the armamentarium of anti-diabetic drugs is expanding, their negative or unknown impacts on bone metabolism limits effectiveness. The inactivation of inositol hexakisphosphate kinase 1 (IP6K1) protects mice from high-fat-diet (HFD)-induced obesity (DIO) and insulin resistance by enhancing thermogenic energy expenditure, but the role of this kinase and the consequences of its inhibition on bone metabolism are unknown. To determine if IP6K1 inhibition in obese mice affords protection against obesity-induced metabolic derangements and bone loss, we maintained 2-month-old mice on a normal chow control diet or HFD under thermal neutral conditions for 100 d. Beginning on day 40, HFD-fed mice were divided into two groups and administered daily injections of vehicle or the pan-IP6K inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine]. HFD-fed mice developed obesity, hyperglycemia, hyperlipidemia, and secondary osteoporosis, while TNP administration protected mice against HFD-induced metabolic and lipid derangements and preserved bone mass, mineral density, and trabecular microarchitecture, which correlated with reduced serum leptin levels, reduced marrow adiposity, and preservation of marrow resident skeletal stem/progenitor cells (SSPCs). TNP also exhibited hypotensive activity, an unrealized benefit of the drug, and its prolonged administration had no adverse impacts on spermatogenesis. Together, these data indicate that the inhibition of IP6K1 using selective inhibitors, such as TNP, may provide an effective strategy to manage obesity and T2DM due to its bone sparing effects.
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影响因子：
2.4
作者：
Kim KC;Shin DH;Lee SY;Im JA;Lee DC
通讯作者：
Lee DC
影响因子：
64.5
作者：
Chakraborty A;Koldobskiy MA;Bello NT;Maxwell M;Potter JJ;Juluri KR;Maag D;Kim S;Huang AS;Dailey MJ;Saleh M;Snowman AM;Moran TH;Mezey E;Snyder SH
通讯作者：
Snyder SH
影响因子：
--
作者：
Chakraborty A
通讯作者：
Chakraborty A
影响因子：
4.1
作者：
Lecka-Czernik, B.;Stechschulte, L. A.;Dowling, A. R.
通讯作者：
Dowling, A. R.
DOI：
10.1073/pnas.0308744101
发表时间：
2004-03-02
影响因子：
11.1
作者：
Elefteriou, F;Takeda, S;Karsenty, G
通讯作者：
Karsenty, G