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Monisha Rajasekaran, Ok-Joo Sul, Eun-Kyung Choi, Ji-Eun Kim, Jae-Hee Suh and Hye-Seon Choi

Obesity is strongly associated with chronic inflammation for which adipose tissue macrophages play a critical role. The objective of this study is to identify monocyte chemoattractant protein-1 (MCP-1, CCL2) as a key player governing M1–M2 macrophage polarization and energy balance. We evaluated body weight, fat mass, adipocyte size and energy expenditure as well as core body temperature of Ccl2 knockout mice compared with wild-type mice. Adipose tissues, differentiated adipocyte and bone marrow-derived macrophages were assessed by qPCR, Western blot analysis and histochemistry. MCP-1 deficiency augmented energy expenditure by promoting browning in white adipose tissue and brown adipose tissue activity via increasing the expressions of Ucp1, Prdm16, Tnfrsf9, Ppargc1a, Nrf1 and Th and mitochondrial DNA copy number. MCP-1 abrogation promoted M2 polarization which is characterized by increased expression of Arg1, Chil3, Il10 and Klf4 whereas it decreased M1 polarization by decreased p65 nuclear translocation and attenuated expression of Itgax, Tnf and Nos2, leading to increased browning of adipocytes. Enhanced M2 polarization and attenuated M1 polarization in the absence of MCP-1 are independent. Collectively, our results suggest that the action of MCP-1 in macrophages modulates energy expenditure by impairing browning in adipose tissue.

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A Amrani, M Jafarian-Tehrani, P Mormède, S Durant, J-M Pleau, F Haour, M Dardenne and F Homo-Delarche


Cytokines, particularly interleukin 1 (IL-1) and tumor necrosis factor, are known to induce hypoglycemia in normal rodents or different experimental models of type II diabetes. We investigated, at the pre-diabetic stage, the effect of short-term administration of murine recombinant interleukin-1α (mrIL-1α) on the levels of glucose, insulin and corticosterone in the non-obese diabetic (NOD) mouse, a spontaneous model of type I diabetes. Two-month-old, pre-diabetic NOD mice of both sexes were insensitive to mrIL-1α (12·5 and 50 μg/kg) 2 h after administration, the time at which the maximal decrease (around 50%) was observed in the C57BL/6 mouse strain. Kinetic studies however showed that mrIL-1α lowered glycemia in both sexes of NOD mice, but the effect was limited and delayed. In the NOD and C57BL/6 strains, mrIL-1α had no influence on insulin levels in females, but significantly increased them in males (P<0·0001). Castration of NOD males abrogated the stimulatory effect of mrIL-1α on insulin secretion. Corticosterone secretion was stimulated by mrIL-1α in both sexes of NOD and C57BL/6 mice, and this effect was faster and greater in NOD females than in C57BL/6 females. The incomplete hypoglycemic response to mrIL-1α in females may be attributed to the anti-insulin effect of glucocorticoids, an effect which can be demonstrated when mrIL-1α is administered to adrenalectomized animals or when mrIL-1α is administered together with the glucocorticoid antagonist RU38486. In NOD males, in contrast, glucocorticoids did not play a major role in the limited hypoglycemic response to mrIL-1α, since RU38486 and adrenalectomy were not able to unmask a hypoglycemic effect. Moreover, NOD mice of both sexes were less sensitive than C57BL/6 mice to the hypoglycemic effect of insulin (2·5 U/kg), which suggests some degree of insulin-resistance in NOD mice. With regard to the effect of IL-1 on NOD mouse glycemia, therefore, these results suggest that glucocorticoids and/or androgens, according to the animal's sex, may induce a state of insulin-resistance.

Journal of Endocrinology (1996) 148, 139–148

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Martina Bugáňová, Helena Pelantová, Martina Holubová, Blanka Šedivá, Lenka Maletínská, Blanka Železná, Jaroslav Kuneš, Petr Kačer, Marek Kuzma and Martin Haluzík

Liraglutide is the glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes mellitus. Recently, it has been demonstrated to decrease cardiovascular morbidity and mortality in patients with type 2 diabetes and high cardiovascular risk. Although the major modes of liraglutide action are well-known, its detailed action at the metabolic level has not been studied. To this end, we explored the effect of 2-week liraglutide treatment in C57BL/6 male mice with obesity and diabetes induced by 13 weeks of high-fat diet using NMR spectroscopy to capture the changes in urine metabolic profile induced by the therapy. The liraglutide treatment decreased body and fat pads weight along with blood glucose and triglyceride levels. NMR spectroscopy identified 11 metabolites significantly affected by liraglutide treatment as compared to high-fat diet-fed control group. These metabolites included ones involved in nicotinamide adenine dinucleotide metabolism, β-oxidation of fatty acids and microbiome changes. Although majority of the metabolites changed after liraglutide treatment were similar as the ones previously identified after vildagliptin administration in a similar mouse model, the changes in creatinine, taurine and trigonelline were specific for liraglutide administration. The significance of these changes and its possible use in the personalization of antidiabetic therapy in humans requires further research.

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K Takeda, K Toda, T Saibara, M Nakagawa, K Saika, T Onishi, T Sugiura and Y Shizuta

Aromatase (CYP19) is a cytochrome P450 enzyme that catalyzes the formation of aromatic C18 estrogens from C19 androgens. It is expressed in various tissues and contributes to sex-specific differences in cellular metabolism. We have generated aromatase-knockout (ArKO) mice in order to study the role of estrogen in the regulation of glucose metabolism. The mean body weights of male ArKO (-/-) mice (n=7) and wild-type littermates (+/+) (n=7) at 10 and 12 weeks of age were 26.7+/-1.9 g vs 26.1+/-0.8 g and 28.8+/-1.4 g vs 26.9+/-1.0 g respectively. The body weights of the ArKO and wild-type mice diverged between 10 and 12 weeks of age with the ArKO males weighing significantly more than their wild-type littermates (P<0.05). The ArKO males showed significantly higher blood glucose levels during an intraperitoneal glucose tolerance test compared with wild-type littermates beginning at 18 weeks of age. By 24 weeks of age, they had higher fasting blood glucose levels compared with wild-type littermates (133.8+/-22.8 mg/dl vs 87.8+/-20.3 mg/dl respectively; P<0.01). An intraperitoneal injection of insulin (0.75 mU insulin/g) caused a continuous decline in blood glucose levels in wild-type mice whereas ArKO males at 18 weeks and older exhibited a rebound increase in glucose levels 30 min after insulin injection. Thus, ArKO male mice appear to develop glucose intolerance and insulin resistance in an age-dependent manner. There was no difference in fasting serum triglyceride and total cholesterol levels between ArKO male mice and wild-type littermates at 13 and 25 weeks of age. However, serum triglyceride and cholesterol levels were significantly elevated following a meal in ArKO mice at 36 weeks of age. Serum testosterone levels in ArKO male mice were continuously higher compared with wild-type littermates. Treatment of ArKO males with 17beta-estradiol improved the glucose response as measured by intraperitoneal glucose and insulin tolerance tests. Treatment with fibrates and thiazolidinediones also led to an improvement in insulin resistance and reduced androgen levels. As complete aromatase deficiency in man is associated with insulin resistance, obesity and hyperlipidemia, the ArKO mouse may be a useful animal model for examining the role of estrogens in the control of glucose and lipid homeostasis.

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T Tsushima, M Arai, O Isozaki, Y Nozoe, K Shizume, H Murakami, N Emoto, M Miyakawa and H Demura


Although endothelins were originally discovered as peptides with vasoconstrictor activity, recent studies have indicated a number of endothelin (ET)-induced hormonal functions in various tissues. We have studied the interaction of endothelins with porcine thyroid cells in culture. Specific binding of 125I-labelled ET-1 was demonstrated in porcine thyroid cells. The binding was displaced equally by unlabelled ET-1 and ET-2, but receptor affinity for ET-3 was lower than that for ET-1 and -2. Scatchard analysis of the data revealed a single class of high-affinity ET-1 receptors with a K d of 0·45 nmol/l and a binding capacity of 2100 sites/cell. SDS-PAGE and autoradiography of 125I-labelled ET-1 cross-linked with thyroid cell membranes demonstrated ET-1 binding sites with an apparent molecular weight of 50 kDa. These results indicated that ET-1 receptors in thyroid cells are type A ET receptors. In association with the presence of ET-1 receptors, porcine thyroid cells responded to ET-1 and ET-2 with an increase in c-fos mRNA expression. Although ET-1 did not affect DNA synthesis stimulated by either EGF or IGF-I, it dose-dependently inhibited TSH-induced iodide uptake and also inhibited iodide uptake stimulated by forskolin and 8-bromo-cAMP. ET-1 had no effect on TSH-stimulated cAMP production. Thus, ET-1 inhibited TSH-induced iodine metabolism by acting at the steps distal to cAMP production. In agreement with a recent report, immunoreactive ET-1 was detected in medium conditioned by porcine thyroid cells. Antibody to ET-1 was found to increase TSH-induced iodide uptake. These results are compatible with the notion that ET-1 negatively regulates TSH-induced iodide uptake in an autocrine manner.

Journal of Endocrinology (1994) 142, 463–470

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Christian K Tipsmark and Steffen S Madsen

It has recently become evident that maintenance of ionic homoeostasis in euryhaline salmonids involves a reciprocal shift in expression of two isoforms of the gill Na+,K+-atpase α-subunit when the surrounding salinity changes. The present study investigated the regulation of this shift between the α1a (freshwater (FW) isoform) and the α1b (seawater (SW) isoform) by cortisol, Gh, prolactin (Prl) and Igf 1. Injection with cortisol into FW salmon increased α1a expression, while Gh had no effect. Conversely, both cortisol and Gh stimulated α1b expression, and a significant synergy was observed. igf1 expression was increased by Gh in both gill and liver, and inhibited by cortisol in the liver. Gill igf1 and gh receptor expression increased in response to cortisol. Injection with Prl into SW salmon compromised their hypo-osmoregulatory performance, selectively reduced the expression of the α1b isoform and decreased enzymatic Na+,K+-atpase activity in the gill. Cortisol and Prl reduced gill and liver igf1 expression, and both hormones stimulated gill igf1 receptor expression. In a short-term experiment with incubation of FW gill cell suspensions, cortisol stimulated α1a and α1b expression, while Igf1 stimulated only α1b. The data elaborate our understanding of Prl and Gh as being antagonists in the control of gill ion regulation, and support a dual role for Gh involving endocrine and paracrine Igf1 action. Gh and Prl may be the decisive stimuli that direct cortisol-aided mitochondrion-rich cell development into either secretory or absorptive types.

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P. J. Miettinen, T. Otonkoski and R. Voutilainen


To understand the development of the human pancreas better, we studied the expression and regulation of insulin, insulin-like growth factor-II (IGF-II) and transforming growth factor-α (TGF-α) genes in the human fetal pancreas and islet-like cell clusters (ICC) from the second trimester human fetuses. Northern blot analysis revealed an abundant expression of IGF-II, insulin and TGF-α mRNAs in the intact pancreas and the cultured ICCs. Furthermore, transcripts for insulin receptor, type-1 and -2 IGF receptors, and GH receptor could be amplified by polymerase chain reaction analysis from the pancreas and the ICCs. With in-situ hybridization, IGF-II mRNA was found in abundance in both the exocrine and endocrine pancreas, exceeding the amount of insulin mRNA. In ICCs, insulin mRNA-containing cells were present as small clusters in the periphery and in the centre of the clusters corresponding to the immunolocation of insulin. The ICCs also contained many epidermal growth factor-, insulin- and type-1 IGF receptor- and TGF-α-positive cells.

When the ICCs were cultured in the presence of various secretagogues, only dibutyryl cyclic AMP was found to up-regulate insulin mRNA (39%; P < 0·05). IGF-II mRNA was also under cyclic AMP-dependent regulation (threefold increase; P = 0·025). Furthermore, blocking the type-1 IGF receptor with a monoclonal receptor antibody drastically reduced insulin expression (87%; P = 0·005) and additionally down-regulated IGF-II mRNA (49%; P = 0·005). IGF-1, IGF-II, TGF-α or epidermal growth factor-receptor antibody had no significant effect on either insulin or IGF-II mRNA. Exogenous TGF-α inhibited the release of insulin by the ICCs. It was concluded that IGF-II and TGF-α may be involved in the regulation of islet growth and differentiation.

Journal of Endocrinology (1993) 138, 127–136

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Zhenping Liu, Per Bendix Jeppesen, Søren Gregersen, Lotte Bach Larsen and Kjeld Hermansen

Chronic hyperglycemia and hyperlipidemia cause deleterious effects on β-cell function. Interestingly, increased circulating amino acid (AA) levels are also a characteristic of the prediabetic and diabetic state. The chronic effects of AAs on β-cell function remain to be determined. Isolated mouse islets and INS-1E cells were incubated with or without excess leucine. After 72 h, leucine increased basal insulin secretion and impaired glucose-stimulated insulin secretion in both mouse islets and INS-1E cells, corroborating the existence of aminoacidotoxicity-induced β-cell dysfunction. This took place concomitantly with alterations in proteins and genes involved in insulin granule transport, trafficking (e.g. collapsin response mediator protein 2 and GTP-binding nuclear protein Ran), insulin signal transduction (proteasome subunit α type 6), and the oxidative phosphorylation pathway (cytochrome c oxidase). Leucine downregulated insulin 1 gene expression but upregulated pancreas duodenum homeobox 1 and insulin 2 mRNA expressions. Importantly, cholesterol (CH) accumulated in INS-1E cells concomitantly with upregulation of enzymes involved in CH biosynthesis (e.g. 3-hydroxy-3-methylglutaryl-CoA reductase, mevalonate (diphospho) decarboxylase, and squalene epoxidase) and LDL receptor, whereas triglyceride content was decreased. Our findings indicate that chronic exposure to elevated levels of leucine may have detrimental effects on both β-cell function and insulin sensitivity. Aminoacidotoxicity may play a pathogenic role in the development of type 2 diabetes.

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Yolanda Diz-Chaves, Manuel Gil-Lozano, Laura Toba, Juan Fandiño, Hugo Ogando, Lucas C González-Matías and Federico Mallo

Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus–pituitary–adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

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E Zoidis, C Ghirlanda-Keller, M Gosteli-Peter, J Zapf and C Schmid

In osteoblasts only the type III Na(+)-dependent phosphate (NaPi) transporter isoforms Pit-1 and Pit-2 have been identified. We tested the effects of extracellular Pi, Ca(2+) and IGF-I on Na(d)Pi transport and Pit-1 or Pit-2 mRNA expression in rat osteoblastic (PyMS) cells. The v(max) of Na(d)Pi transport was higher in cells kept in Pi-free, serum-free medium for 24 h than in controls at 1 mM Pi (2.47+/-0.20 vs 1.83+/-0.17 nmol/mg protein x 10 min). The apparent affinity constant (K(M)) for Pi remained unchanged. Pi withdrawal for 24 h did not impair cell viability whereas increasing the extracellular Pi to 5 mM resulted in cell death. Pit-1 (but not Pit-2) mRNA was upregulated following Pi deprivation, Ca(2+) treatment or after treatment with 1 nM IGF-I, known to stimulate Na(d)Pi transport and cell proliferation. IGF-I also stimulated Na(d)Pi transport and Pit-1 mRNA in primary rat calvarial osteoblasts. Expression of Pit-1 mRNA in vivo and the coordinate regulation of Pit-1 mRNA and Pi transport in osteoblastic cells suggest that Pit-1 is a candidate transporter of physiological relevance in bone.