Increased PTHrP and Decreased Estrogens Alter Bone Turnover but Do Not Reproduce the Full Effects of Lactation on the Skeleton
Laleh Ardeshirpour, Susan Brian, Pamela Dann, Joshua VanHouten, John Wysolmerski
2010
Endocrine reviews
Fetal nutrient and growth restriction is associated with development of type 2 diabetes. Although the exact mechanisms responsible for this association remain debated, intrauterine and/or postnatal maldevelopment of -cell mass has been proposed as a potential mechanism. To address this hypothesis, -cell mass development and turnover was assessed in rats exposed to either intrauterine and/or postnatal caloric/growth restriction. In total, four groups of male and female Sprague Dawley rats (n ϭ
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... 69) were developed and studied: 1) control rats, i.e. control mothers rearing control pups; 2) intrauterine calorically and growth-restricted rats, i.e. 50% prenatal calorically restricted pups cross-fostered to control mothers; 3) postnatal calorically and growth-restricted rats, i.e. 50% calorically restricted mothers rearing pups born to control mothers; and 4) prenatal and postnatal calorically and growth restricted rats, i.e. 50% calorically restricted mothers rearing intrauterine 50% calorically restricted pups. Intrauterine growth restriction resulted in approximately 45% reduction of postnatal -cell fractional area and mass characterized by reduced rate of -cell replication and decreased evidence of neogenesis. In contrast, -cell fractional area and weight-adjusted -cell mass in postnatal growth restriction was approximately 30% higher than in control rats. Rats exposed to both intrauterine and postnatal caloric and growth restriction demonstrated approximately 80% decrease in -cell mass, reduction in -cell replication, and decreased evidence of neogenesis compared with control. Neither intrauterine nor postnatal caloric restriction significantly affected the rate of -cell apoptosis. These data support the hypothesis that intrauterine maldevelopment of -cell mass may predict the increased risk of type 2 diabetes in adult life. Endocrinology, During lactation, calcium is mobilized from the maternal skeleton to supply the breast for milk production. This results in rapid but fully reversible bone loss. Prior studies have suggested that PTHrP, secreted from the breast, and estrogen deficiency, due to sucklinginduced central hypogonadism, combine to trigger bone resorption. To determine whether this combination was sufficient to explain bone loss during lactation, we raised PTHrP levels and decreased levels of estrogens in nulliparous mice. PTHrP was infused via osmotic minipumps and estrogens were decreased either by using leuprolide, a long-acting GnRH agonist, or by surgical ovariectomy (OVX). Bone mineral density declined by 23.2 Ϯ 1.3% in the spine and 16.8 Ϯ 1.9% in the femur over 10 d of lactation. This was accompanied by changes in trabecular architecture and an increase in both osteoblast and osteoclast numbers. OVX and PTHrP infusion both induced a modest decline in bone mineral density over 10 d, but leuprolide treatment did not. The combination of OVX and PTHrP was more effective than either treatment alone, but there was no interaction between PTHrP and leuprolide. None of the treatments reproduced the same degree of bone loss caused by lactation. However, both forms of estrogen deficiency led to an increase in osteoclasts, whereas infusion of PTHrP increased both osteoblasts and osteoclasts. Therefore, although the combination of PTHrP and estrogen deficiency contributes to bone loss, it is insufficient to reproduce the full response of the skeleton to lactation, suggesting that other factors also regulate bone metabolism during this period. Endocrinology, GH deficiency is known to be clinically associated with a high incidence of nonalcoholic fatty liver disease, and this can be reversed by GH administration. Here we investigated the mechanistic basis for this phenomenon using engineered male mice lacking different signaling elements of the GH receptor, hepatic stat5a/b Ϫ/Ϫ mice and a mouse hepatoma line. We found deficient GH-dependent signal transducer and activator of transcription (STAT)-5 signaling correlates with steatosis, and through microarray analysis, quantitative PCR, and chromatin immunoprecipitation, identifies putative targets of STAT5 signaling responsible for the steatosis seen on a normal diet. These targets were verified with liverspecific stat5a/b deletion in vivo, and in vitro we show that dominantnegative (DN) STAT5 increases lipid uptake in a mouse hepatoma line. Because loss of STAT5 signaling results in elevated STAT1 and STAT3 activity and intracellular lipid accumulation, we have used the hepatoma line DN-STAT5a/b, DN-STAT1, CA-STAT3, or addition of oleate/palmitate to assign which of these apply to individual targets in active STAT5 deficiency. These findings and published mouse models of steatosis enable us to propose elevated cd36, ppar␥, and pgc1␣/ expression as primary instigators of the steatosis along with elevated fatty acid synthase, lipoprotein lipase, and very low-density lipoprotein receptor expression. Decreased fgf21 and insig2 expression may also contribute. In conclusion, despite normal plasma free
doi:10.1210/edrv.31.6.9976
fatcat:z4ot5ixnobeeza33tuwurrrz5y