| 1. |
|
|
| 2. |
- Iglesias, José, et al.
(författare)
-
PPARβ/δ affects pancreatic β cell mass and insulin secretion in mice
- 2012
-
Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 122:11, s. 4105-4117
-
Tidskriftsartikel (refereegranskat)abstract
- PPARβ/δ protects against obesity by reducing dyslipidemia and insulin resistance via effects in muscle, adipose tissue, and liver. However, its function in pancreas remains ill defined. To gain insight into its hypothesized role in β cell function, we specifically deleted Pparb/d in the epithelial compartment of the mouse pancreas. Mutant animals presented increased numbers of islets and, more importantly, enhanced insulin secretion, causing hyperinsulinemia. Gene expression profiling of pancreatic β cells indicated a broad repressive function of PPARβ/δ affecting the vesicular and granular compartment as well as the actin cytoskeleton. Analyses of insulin release from isolated PPARβ/δ-deficient islets revealed an accelerated second phase of glucose-stimulated insulin secretion. These effects in PPARβ/δ-deficient islets correlated with increased filamentous actin (F-actin) disassembly and an elevation in protein kinase D activity that altered Golgi organization. Taken together, these results provide evidence for a repressive role for PPARβ/δ in β cell mass and insulin exocytosis, and shed a new light on PPARβ/δ metabolic action.
|
|
| 3. |
- Ohlsson, Claes, 1965, et al.
(författare)
-
Estrogen receptor-α expression in neuronal cells affects bone mass.
- 2012
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 109:3, s. 983-988
-
Tidskriftsartikel (refereegranskat)abstract
- It has generally been assumed that bone mass is controlled by endocrine mechanisms and the local bone environment. Recent findings demonstrate that central pathways are involved in the regulation of bone mass. Estrogen is involved in the regulation of bone homeostasis and the CNS is also a target for estrogen actions. The aim of this study was to investigate in vivo the role of central estrogen receptor-α (ERα) expression for bone mass. Nestin-Cre mice were crossed with ERα(flox) mice to generate mice lacking ERα expression specifically in nervous tissue (nestin-ERα(-/-)). Bone mineral density was increased in both the trabecular and cortical bone compartments in nestin-ERα(-/-) mice compared with controls. Femoral bone strength was increased in nestin-ERα(-/-) mice, as demonstrated by increased stiffness and maximal load of failure. The high bone mass phenotype in nestin-ERα(-/-) mice was mainly caused by increased bone formation. Serum leptin levels were elevated as a result of increased leptin expression in white adipose tissue (WAT) and slightly increased amount of WAT in nestin-ERα(-/-) mice. Leptin receptor mRNA levels were reduced in the hypothalamus but not in bone. In conclusion, inactivation of central ERα signaling results in increased bone mass, demonstrating that the balance between peripheral stimulatory and central inhibitory ERα actions is important for the regulation of bone mass. We propose that the increased bone mass in nestin-ERα(-/-) mice is mediated via decreased central leptin sensitivity and thereby increased secretion of leptin from WAT, which, in turn, results in increased peripheral leptin-induced bone formation.
|
|
| 4. |
- Windahl, Sara H, 1971, et al.
(författare)
-
Estrogen Receptor-alpha is required for the Osteogenic Response to mechanical loading in a Ligand-Independent manner involving its activation function 1 but Not 2
- 2013
-
Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 28:2, s. 291-301
-
Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor-alpha (ER alpha) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERa domains for the osteogenic response to mechanical loading, gene-targeted mouse models with (1) a complete ERa inactivation (ER alpha(-/-)), (2) specific inactivation of activation function 1 (AF-1) in ER alpha (ER alpha AF-1(0)), or (3) specific inactivation of ER alpha AF-2 (ER alpha AF- 2(0)) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ER alpha(-/-) mice displayed a severely reduced osteogenic response to loading with changes in cortical area (-78% +/- 15%, p < 0.01) and periosteal BFR (-81% +/- 9%, p < 0.01) being significantly lower than in wild-type (WT) mice. ER alpha AF-1(0) mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area -40% +/- 11%, p < 0.05 and periosteal BFR -41% +/- 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ER alpha AF-2(0) mice. Mechanical loading of transgenic estrogen response element (ERE)-luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE-mediated pathways. In conclusion, ERa is required for the osteogenic response to mechanical loading in a ligand-independent manner involving AF-1 but not AF-2. (C) 2013 American Society for Bone and Mineral Research.
|
|
