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It has been demonstrated in the rat that on the day of prooestrus there is a critical period for the initiation of the release of the 'ovulating gonadotrophic complex' from the pituitary gland (Everett, 1952). Thus, in animals kept under controlled lighting conditions with illumination from 5 a.m. to 7 p.m. the critical period is between 2 and 4 p.m., ovulation occurring between 1 and 2.30 a.m. the next day.
Bourdel (1961) showed that rabbit anti-ovine-LH serum could neutralize endogenous LH in immature female rats, and more recently Bourdel & Li (1963) found that this antiserum, when injected into adult female rats daily for 12 days beginning 36 hr. in advance of presumed oestrus, could suppress this oestrus and subsequent ones. If the first injection were given only 12—16 hr. in advance, the first expected oestrus occurred normally, although subsequent oestrous periods were suppressed. Similarly, Young, Nasser & Hayashida (1963)
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
Search for other papers by Kelly D McCall in
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
Search for other papers by Leonard D Kohn in
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Wnt binding to cell surface receptors can activate a ‘canonical’ pathway that increases cellular β-catenin or a ‘noncanonical’ Ca++ pathway which can increase protein kinase C (PKC) activity. Although components of both Wnt/β-catenin-signaling pathways exist in thyrocytes, their biological role is largely unknown. In evaluating the biological role of Wnt signaling in differentiated FRTL-5 thyroid cells, we showed that TSH increased canonical Wnt-1 but, surprisingly, decreased the active form of β-catenin. Transient overexpression of Wnt-1 or β-catenin in FRTL-5 cells increased active β-catenin (ABC), decreased thyroperoxidase (TPO) mRNA, and suppressed TPO-promoter activity. The target of β-catenin suppressive action was a consensus T cell factor/lymphoid enhancing factor (TCF/LEF)-binding site 5′-A/T A/T CAAAG-3′, −137 to −129 bp on the rat TPO promoter. β-Catenin overexpression significantly increased complex formation between β-catenin/TCF-1 and an oligonucleotide containing the TCF/LEF sequence, suggesting that the β-catenin/TCF-1 complex acts as a transcriptional repressor of the TPO gene. Stable over-expression of Wnt-1 in FRTL-5 cells significantly increased the growth rate without increasing β-catenin levels. Increased growth was blunted by a PKC inhibitor, staurosporin. Wnt-1 overexpression increased serine phosphorylation, without affecting tyrosine phosphorylation, of signal transducers and activators of transcription 3 (STAT3) protein. In addition, these final results suggest that TSH-induced increase in Wnt-1 levels in thyrocytes contributes to enhanced cellular growth via a PKC pathway that increases STAT3 serine phosphorylation and activation, whereas TSH-induced decrease in activation of β-catenin simultaneously relieves transcriptional suppression of TPO. We hypothesize that Wnt signaling contributes to the ability of TSH to simultaneously increase cell growth and functional, thyroid-specific, gene expression.
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Visceral adipocytes and associated macrophages produce and release excessive amounts of biologically active inflammatory cytokines via the portal and systemic vascular system, which induce insulin resistance in insulin target tissues such as fat, liver, and muscle. Free fatty acids (FFAs) absorbed via the portal system or released from adipocytes also induce insulin resistance. In this report, we show that phenylmethimazole (C10) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells (3T3L1 adipocytes) without affecting insulin-stimulated AKT signaling. In addition, C10 inhibits palmitate-induced IL6 and iNos up-regulation in both 3T3L1 adipocytes and RAW 264.7 macrophages, LPS-induced NF-κB and IFN-β activation in 3T3L1 cells, and LPS-induced iNos, Ifn- β, Il1 β, Cxcl10, and Il6 expression in RAW 264.7 macrophages. C10 also blocks palmitate-induced Socs-3 up-regulation and insulin receptor substrate-1 (IRS-1) serine 307 phosphorylation in 3T3L1 adipocytes. Additionally, we show for the first time that although palmitate increases IRS-1 serine 307 phosphorylation in 3T3L1 adipocytes, AKT serine 473 phosphorylation is enhanced, not reduced, by palmitate. These results suggest that through inhibition of FFA-mediated signaling in adipocytes and associated macrophages, as well as possibly other insulin target cells/tissues (i.e. non-immune cells), C10 might be efficacious to prevent or reverse cytokine-induced insulin resistance seen in obesity-related insulin resistance and type 2 diabetes mellitus.
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SUMMARY
A system for perfusing in vitro the mid-term human pregnant uterus containing the entire foeto-placental unit is described. After termination by hysterectomy, circulation was established within 15 min by cannulation of the uterine arteries. In two experiments the foetal heart rate remained reasonably steady during the perfusion (107 and 127 min respectively). The rates of secretion of pregnenolone and progesterone into the uterine veins were within the range calculated for the period of gestation. Conversion of [4-14C]cholesterol to pregnenolone and progesterone was observed in both experiments although in neither could it account for the total secretion of progesterone.
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Abstract
To define the hormonal influences that are directly involved in the hair follicle cycles of animals with differing patterns of fibre growth and moulting, we have investigated the possible presence of IGF-I and melatonin receptors on the dermis and hair follicles of cashmere and Angora goats, sampled in February, March and June, using quantitative in vitro autoradiography. The presence of IGF-I receptors in the dermis of both breeds of goat was determined using cryostat sections incubated with 50 pm 125I-labelled IGF-I in the presence or absence of 50 nm IGF-I. Sections of the growing tip of deer antlers containing the cartilaginous zone, a tissue known to contain high concentrations of specific IGF-I receptors, were used as a positive control. As the production of antler velvet uniquely involves the generation of hair follicles de novo, the presence of IGF-I receptors in the velvet-producing region was also investigated. In both breeds of goat, specific 125I-IGF-I binding was localised over the inner and outer root sheath, the matrix, the germinal matrix, the dermal papilla and the sebaceous glands and satisfied the basic kinetic criteria considered to be representative of a specific IGF-I receptor. Analysis of saturation isotherms using a one-site binding model revealed dissociation constants (Kd) in the range 0·1–0·9 nm and theoretical maximal numbers of binding sites (Bmax) between 21·4 and 45·6 fmol/mg tissue. Kd and Bmax values derived from cashmere and Angora goats sampled at different times of the year did not differ significantly between breeds or sampling times. Specific 125I-IGF-I binding was also localised to the developing follicles on the deer antler dermis. The presence of melatonin receptors within the goat dermis was also investigated. Sections were incubated with 100 pm 2-[125I]iodomelatonin with or without 0·1 μm melatonin, along with sections of sheep pars tuberalis which are known to contain high levels of high-affinity melatonin receptors. No displaceable 2-[125I]iodomelatonin binding was found on any sections of the cashmere or Angora skin analysed. It is therefore concluded that melatonin receptors are not present on the hair follicles or associated structures. IGF-I receptors are present on the hair follicle and sebaceous gland and may be involved in the growth of both seasonally and non-seasonally produced fibre and in the development of antler velvet.
Journal of Endocrinology (1996) 151, 55–63
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SUMMARY
Radioreceptor assays for prolactin-like (lactogenic) activity and growth hormone (GH)-like activity have been used to study concentrations of caprine placental lactogen (PL) in the circulation during pregnancy. Both lactogenic and GH-like activities increased from less than 100 ng/ml (ovine prolactin- and human GH-equivalents) about 60 days after mating to reach peak levels (400–1600 ng/ml) between days 110 and 130 of pregnancy. The levels of both activities increased in essentially the same fashion but during the last 15 days of pregnancy, lactogenic activity declined less than GH-like activity. This divergence was most pronounced at parturition when levels of lactogenic activity increased (∼ 700 ng/ml) despite very low (< 200 ng/ml) levels of GH-like activity being measured and this probably reflected increased secretion of pituitary prolactin near parturition. When serum from a pregnant goat or a simple alkaline extract of placental cotyledons was fractionated on a column packed with Sephadex G-100, lactogenic and GH-like activities eluted together with distribution coefficients of approximately 0·5–0·6. The possibility that caprine PL serves physiologically as a luteotrophin and/or mammotrophin during pregnancy in goats is discussed.
Diabetes Institute, Ohio University, Athens, Ohio, USA
Department of Biological Sciences, Ohio University, Athens, Ohio, USA
Molecular & Cellular Biology Program, College of Arts and Sciences, Ohio University, Athens, Ohio, USA
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Diabetes Institute, Ohio University, Athens, Ohio, USA
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Diabetes Institute, Ohio University, Athens, Ohio, USA
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Molecular & Cellular Biology Program, College of Arts and Sciences, Ohio University, Athens, Ohio, USA
Biomedical Engineering Program, Ohio University, Athens, Ohio, USA
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Department of Biomedical Sciences, Ohio University, Athens, Ohio, USA
The Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
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Diabetes Institute, Ohio University, Athens, Ohio, USA
The Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
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Diabetes Institute, Ohio University, Athens, Ohio, USA
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Diabetes Institute, Ohio University, Athens, Ohio, USA
Department of Biological Sciences, Ohio University, Athens, Ohio, USA
Molecular & Cellular Biology Program, College of Arts and Sciences, Ohio University, Athens, Ohio, USA
Biomedical Engineering Program, Ohio University, Athens, Ohio, USA
Department of Biomedical Sciences, Ohio University, Athens, Ohio, USA
Search for other papers by Kelly D McCall in
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Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases and has become the leading chronic liver disease worldwide. High-fat (HF) diets promote an increased uptake and storage of free fatty acids (FFAs) and triglycerides (TGs) in hepatocytes, which initiates steatosis and induces lipotoxicity, inflammation and insulin resistance. Activation and signaling of Toll-like receptor 4 (TLR4) by FFAs induces inflammation evident in NAFLD and insulin resistance. Currently, there are no effective treatments to specifically target inflammation associated with this disease. We have established the efficacy of phenylmethimazole (C10) to prevent lipopolysaccharide and palmitate-induced TLR4 signaling. Because TLR4 is a key mediator in pro-inflammatory responses, it is a potential therapeutic target for NAFLD. Here, we show that treatment with C10 inhibits HF diet-induced inflammation in both liver and mesenteric adipose tissue measured by a decrease in mRNA levels of pro-inflammatory cytokines. Additionally, C10 treatment improves glucose tolerance and hepatic steatosis despite the development of obesity due to HF diet feeding. Administration of C10 after 16 weeks of HF diet feeding reversed glucose intolerance, hepatic inflammation, and improved hepatic steatosis. Thus, our findings establish C10 as a potential therapeutic for the treatment of NAFLD.
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ABSTRACT
The development of the reproductive system was studied in juvenile starlings during the acquisition of photosensitivity, the attainment of sexual maturation after photostimulation and the subsequent onset of photorefractoriness, using immunohistochemistry for LHRH and radioimmunoassay measurements of hypothalamic, pituitary and plasma hormone concentrations. The first stage of sexual development induced by exposure of photorefractory immature starlings to short days (8 h light:16 h darkness; 8L:16D) was characterized by a decrease in pituitary prolactin content within 1 week and an increase in hypothalamic LHRH content, in the size of the LHRH perikarya and in the intensity of immunostaining in the median eminence in 4–6 weeks. Sexual maturation occurring after exposure to long days (18L:6D) was associated with further increases in LHRH content and cell size, and increases in LH and prolactin concentrations. During testicular regression, LHRH perikarya were reduced in size and staining intensity but LHRH immunostaining in the median eminence and content in the hypothalamus remained high until gonadal regression was almost complete. Prolactin levels were maximal during testicular regression. These results suggest that gonadal regression is initiated by a reduction in LHRH synthesis and possibly, in addition, an external inhibitory influence on LHRH release. Hypothalamic LHRH content eventually declined and LHRH immunostaining in the median eminence was much reduced in fully photorefractory starlings maintained under long days.
Journal of Endocrinology (1989) 122, 255–268
