Early onset of obesity induces reproductive deficits in female rats

The incidence of obesity is increasing rapidly all over the world and results in numerous health detriments, including disruptions in reproduction. However, the mechanisms by which excess body fat interferes with reproductive functions are still not fully understood. After weaning, female rats were treated with a cafeteria diet or a chow diet (control group). Biometric and metabolic parameters were evaluated in adulthood. Reproductive parameters, including estradiol, progesterone, LH and prolactin during the proestrus afternoon, sexual behavior, ovulation rates and histological analysis of ovaries were also evaluated. Cafeteria diet was able to induce obesity in female rats by increasing body and fat pad weight, which resulted in increased levels of triglycerides, total cholesterol, LDL and induced insulin resistance. The cafeteria diet also negatively affected female reproduction by reducing the number of oocytes and preantral follicles, as well as the thickness of the follicular layer. Obese females did not show preovulatory progesterone and LH surges, though plasma estradiol and prolactin showed preovulatory surges similar to control rats. Nevertheless, sexual receptiveness was not altered by cafeteria diet. Taken together, our results suggest that the cafeteria diet administered from weaning age was able to induce obesity and reduce the reproductive capability in adult female rats, indicating that this obesity model can be used to better understand the mechanisms underlying reproductive dysfunction in obese subjects. (C) 2012 Elsevier Inc. All rights reserved.Fundacao Araucaria de Apoio ao Desenvolvimento Cientifico e Tecnologico do Estado do ParanaFundacao Araucaria de Apoio ao Desenvolvimento Cientifico e Tecnologico do Estado do ParanaConselho Nacional para o Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional para o Desenvolvimento Cientifico e Tecnologico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Secretaria de Ciencia, Tecnologia e Ensino Superior do Estado do ParanaSecretaria de Ciencia, Tecnologia e Ensino Superior do Estado do Paran

Duodenal-jejunal bypass normalizes pancreatic islet proliferation rate and function but not hepatic steatosis in hypothalamic obese rats

Modifications in life-style and/or pharmacotherapies contribute to weight loss and ameliorate the metabolic profile of diet-induced obese humans and rodents. Since these strategies fail to treat hypothalamic obesity, we have assessed the possible mechanisms by which duodenal-jejunal bypass (DJB) surgery regulates hepatic lipid metabolism and the morphophysiology of pancreatic islets, in hypothalamic obese (HyO) rats. During the first 5 days of life, male Wistar rats received subcutaneous injections of monosodium glutamate (4 g/kg body weight, HyO group), or saline (CTL). At 90 days of age, HyO rats were randomly subjected to DJB (HyO DJB group) or sham surgery (HyO Sham group). HyO Sham rats were morbidly obese, insulin resistant, hypertriglyceridemic and displayed higher serum concentrations of non-esterified fatty acids (NEFA) and hepatic triglyceride (TG). These effects were associated with higher expressions of the lipogenic genes and fatty acid synthase (FASN) protein content in the liver. Furthermore, hepatic genes involved in β-oxidation and TG export were down-regulated in HyO rats. In addition, these rats exhibited hyperinsulinemia, β-cell hypersecretion, a higher percentage of islets and β-cell area/pancreas section, and enhanced nuclear content of Ki67 protein in islet-cells. At 2 months after DJB surgery, serum concentrations of TG and NEFA, but not hepatic TG accumulation and gene and protein expressions, were normalized in HyO rats. Insulin release and Ki67 positive cells were also normalized in HyO DJB islets. In conclusion, DJB decreased islet-cell proliferation, normalized insulinemia, and ameliorated insulin sensitivity and plasma lipid profile, independently of changes in hepatic metabolism

Early Onset Of Obesity Induces Reproductive Deficits In Female Rats

The incidence of obesity is increasing rapidly all over the world and results in numerous health detriments, including disruptions in reproduction. However, the mechanisms by which excess body fat interferes with reproductive functions are still not fully understood. After weaning, female rats were treated with a cafeteria diet or a chow diet (control group). Biometric and metabolic parameters were evaluated in adulthood. Reproductive parameters, including estradiol, progesterone, LH and prolactin during the proestrus afternoon, sexual behavior, ovulation rates and histological analysis of ovaries were also evaluated. Cafeteria diet was able to induce obesity in female rats by increasing body and fat pad weight, which resulted in increased levels of triglycerides, total cholesterol, LDL and induced insulin resistance. The cafeteria diet also negatively affected female reproduction by reducing the number of oocytes and preantral follicles, as well as the thickness of the follicular layer. Obese females did not show preovulatory progesterone and LH surges, though plasma estradiol and prolactin showed preovulatory surges similar to control rats. Nevertheless, sexual receptiveness was not altered by cafeteria diet. Taken together, our results suggest that the cafeteria diet administered from weaning age was able to induce obesity and reduce the reproductive capability in adult female rats, indicating that this obesity model can be used to better understand the mechanisms underlying reproductive dysfunction in obese subjects. © 2012 Elsevier Inc.105511041111Spiegelman, B.M., Flier, J.S., Obesity and the regulation of energy balance (2001) Cell, 104, pp. 531-543Mayes, J.S., Watson, G.H., Direct effects of sex steroids hormones on adipose tissues and obesity (2004) Obes Rev, 5, pp. 197-216Rogers, J., Mitchell, G.W., The relation of obesity to menstrual disturbances (1952) N Engl J Med, 247 (2), pp. 53-55Pasquali, R., Casimirri, F., The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women (1993) Clin Endocrinol, 39 (1), pp. 1-16Tortoriello, D.V., McMinn, J., Chua, S.C., Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice (2004) Endocrinology, 45 (3), pp. 1238-1247Hall, L.F., Neubert, A.G., Obesity and pregnancy (2005) Obstet Gynecol Surv, 60 (4), pp. 253-260Brannian, J.D., Furman, G.M., Diggins, M., Declining fertility in the lethal yellow mouse is related to progressive hyperleptinemia and leptin resistance (2005) Reprod Nutr Dev, 45 (2), pp. 143-150Rittmaster, R.S., Desewal, M., Lehman, L., The role of adrenal hyperandrogenism, insulin resistance, and obesity in the pathogenesis of polycystic ovarian syndrome (1993) J Clin Endocrinol Metab, 76, pp. 1295-1300Douchi, T., Kuwahata, R., Yamamoto, S., Oki, T., Yamasaki, H., Nagata, Y., Relationship of upper obesity to menstrual disorders (2002) Acta Obstet Gynecol Scand, 81, pp. 147-150Chopra, M., Galbraith, S., Damton-Hill, I., A global response to a global problem: the epidemic of overnutrition (2002) Bull World Health Organ, 80 (12), pp. 952-958Yura, S., Ogawa, Y., Sagawa, N., Masuzaki, H., Itoh, H., Ebihara, K., Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin (2000) J Clin Invest, 105 (6), pp. 749-755Lake, J.K., Power, C., Cole, T.J., Women's reproductive health: the role of body mass index in early and adult life (1997) Int J Obes Relat Metab Disord, 21 (6), pp. 432-438Prada, P.O., Zecchin, H.G., Gasparetti, A.L., Torsoni, M.A., Ueno, M., Hirata, A.E., Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1ser307 phosphorylation in a tissue-specific fashion (2005) Endocrinology, 146 (3), pp. 1576-1587Freeman, M.E., The neuroendocrine control of the ovarian cycle of the rat (1994) Physiology of reproduction, 45, pp. 613-658. , Raven Press, New York, E. Knobil, Neill (Eds.)Gomes, C.M., Raineki, C., Ramos de Paula, P., Severino, G.S., Helena, C.V., Anselmo-Franci, J.A., Neonatal handling and reproductive function in female rats (2005) J Endocrinol, 184 (2), pp. 435-445Sodersten, P., Hansen, S., Effects of oestradiol and progesterone on the induction and duration of sexual receptivity in cyclic female rats (1977) J Endocrinol, 74 (3), pp. 477-485Pfaus, J.G., Shadiack, A., Van Soest, T., Tse, M., Molinoff, P., Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist (2004) Proc Natl Acad Sci U S A, 101 (27), pp. 10201-10204Poletini, M.O., Szawka, R.E., Freitas Marcon, R.M., Veiga, M.D., Franci, C.R., Anselmo-Franci, J.A., A method to study preovulatory surges of gonadotropins (2003) Brain Res Brain Res Protoc, 12 (1), pp. 41-48. , Endocrinology 146(3): 1576-1587Harms, P.G., Ojeda, S.R., A rapid and simple procedure for chronic cannulation of the rat jugular vein (1974) J Appl Physiol, 36 (3), pp. 391-392Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man (1985) Diabetologia, 28 (7), pp. 412-419Lara, H.E., Dissen, G.A., Leyton, V., Paredes, A., Fuenzalida, H., Fieldler, J.L., An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat (2000) Endocrinology, 141 (3), pp. 1059-1072Richards, J.S., Maturation of ovarian follicles: actions and interactions of pituitary and ovarian hormones on follicular cell differentiation (1980) Physiol Rev, 60 (1), pp. 51-89Bao, B., Kumar, N., Karp, R.M., Garverick, H.A., Sundaram, K., Estrogen receptor-beta expression in relation to the expression of luteinizing hormone receptor and cytochrome P450 enzymes in rat ovarian follicles (2000) Biol Reprod, 63 (6), pp. 1747-1755Micevych, P., Sinchak, K., Mills, R.H., Tao, L., LaPolt, P., Lu, J.K., The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats (2003) Neuroendocrinology, 78 (1), pp. 29-35Wildt, L., Hausler, A., Hutchison, J.S., Marshall, G., Knobil, E., Estradiol as a gonadotropin releasing hormone in the rhesus monkey (1981) Endocrinology, 108 (5), pp. 2011-2013Moenter, S.M., Caraty, A., Karsch, F.J., The estradiol-induced surge of gonadotropin-releasing hormone in the ewe (1990) Endocrinology, 127 (3), pp. 1375-1384Freeman, M.E., Kanyicska, B., Lerant, A., Nagy, G., Prolactin: structure, function, and regulation of secretion (2000) Physiol Rev, 80 (4), pp. 1523-1631. , ReviewMcNatty, K.P., Sawers, R.S., McNeilly, A.S., A possible role for prolactin in control of steroid secretion by the human Graafian follicle (1974) Nature, 250 (5468), pp. 653-655Uilenbroek, J.T., van der Schoot, P., den Besten, D., Lankhorst, R.R., A possible direct effect of prolactin on follicular activity (1982) Biol Reprod, 27 (5), pp. 1119-1125Oktem, O., Oktay, K., The ovary: anatomy and function throughout human life (2008) Ann N Y Acad Sci, 1127, pp. 1-9. , ReviewMattioli, M., Barboni, B., Turriani, M., Galeati, G., Zannoni, A., Castellani, G., Follicle activation involves vascular endothelial growth factor production and increased blood vessel extension (2001) Biol Reprod, 65 (4), pp. 1014-1019Kretschmer, B.D., Schelling, P., Beier, N., Liebscher, C., Treutel, S., Krüger, N., Modulatory role of food, feeding regime and physical exercise on body weight and insulin resistance (2005) Life Sci, 76 (14), pp. 1553-1573Fried, S.K., Rao, S.P., Sugars, hypertriglyceridemia, and cardiovascular disease (2003) Am J Clin Nutr, 78 (4), pp. 873S-880SMortola, J.F., Sathanandan, M., Pavlou, S., Dahl, K.D., Hsueh, A.J., Rivier, J., Suppression of bioactive and immunoreactive follicle-stimulating hormone and luteinizing hormone levels by a potent gonadotropin-releasing hormone antagonist: pharmacodynamic studies (1989) Fertil Steril, 51 (6), pp. 957-963Poretsky, L., Cataldo, N.A., Rosenwaks, Z., Giudice, L.C., The insulin-related ovarian regulatory system in health and disease (1999) Endocr Rev, 20 (4), pp. 535-582Billig, H., Furuta, I., Hsueh, A.J., Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis (1993) Endocrinology, 133 (5), pp. 2204-2212Willis, D., Mason, H., Gilling-Smith, C., Franks, S., Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries (1996) J Clin Endocrinol Metab, 81 (1), pp. 302-309Brüning, J.C., Gautam, D., Burks, D.J., Gillette, J., Schubert, M., Orban, P.C., Role of brain insulin receptor in control of body weight and reproduction (2000) Science, 289 (5487), pp. 2122-2125Gosman, G.G., Katcher, H.I., Legro, R.S., Obesity and the role of gut and adipose hormones in female reproduction (2006) Hum Reprod Update, 12 (5), pp. 585-601. , ReviewMaffei, M., Halaas, J., Ravussin, E., Pratley, R.E., Lee, G.H., Zhang, Y., Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects (1995) Nat Med, 11, pp. 1155-1161Moschos, S., Chan, J.L., Mantzoros, C.S., Leptin and reproduction: a review (2002) Fertil Steril, 77 (3), pp. 433-444. , ReviewBajari, T.M., Nimpf, J., Schneider, W.J., Role of leptin in reproduction (2004) Curr Opin Lipidol, 15 (3), pp. 315-319. , ReviewDuggal, P.S., Van Der Hoek, K.H., Milner, C.R., Ryan, N.K., Armstrong, D.T., Magoffin, D.A., The in vivo and in vitro effects of exogenous leptin on ovulation in the rat (2000) Endocrinology, 141 (6), pp. 1971-1976Spicer, L.J., Francisco, C.C., The adipose obese gene product, leptin: evidence of a direct inhibitory role in ovarian function (1997) Endocrinology, 138 (8), pp. 3374-3379Agarwal, S.K., Vogel, K., Weitsman, S.R., Magoffin, D.A., Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary (1999) J Clin Endocrinol Metab, 84 (3), pp. 1072-1076Pasquali, R., Gambineri, A., Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age (2006) Ann N Y Acad Sci, 1092, pp. 158-174. , ReviewSaigal, C.S., Obesity and erectile dysfunction: common problems, common solution? (2004) JAMA, 291 (24), pp. 3011-3012Esposito, K., Di Palo, C.C., Marfella, R., Giugliano, D., The effect of weight loss on endothelial functions in obesity: response to Sciacqua et al (2003) Diab Care, 26 (10), pp. 2968-2969Kolotkin, R.L., Binks, M., Crosby, R.D., Østbye, T., Gress, R.E., Adams, T.D., Obesity and sexual quality of life (2006) Obesity (Silver Spring), 14 (3), pp. 472-479Bajos, N., Wellings, K., Laborde, C., Moreau, C., Sexuality and obesity, a gender perspective: results from French national random probability survey of sexual behaviours (2010) BMJ, 340, pp. c2573. , CSF GroupKarkanias, G.B., Morales, J.C., Li, C.S., Deficits in reproductive behavior in diabetic female rats are due to hypoinsulinemia rather than hyperglycemia (1997) Horm Behav, 32 (1), pp. 19-29Levi, J.E., Weinberg, T., Pregnancy in alloxan diabetic rats (1949) Proc Soc Exp Biol Med, 72 (3), pp. 658-662McEwen, B.S., Neural gonadal steroid actions (1981) Science, 211 (4488), pp. 1303-1311. , ReviewEtgen, A.M., Chu, H.P., Fiber, J.M., Karkanias, G.B., Morales, J.M., Hormonal integration of neurochemical and sensory signals governing female reproductive behavior (1999) Behav Brain Res, 105 (1), pp. 93-103Mathews, D., Edwards, D.A., The ventromedial nucleus of the hypothalamus and the hormonal arousal of sexual behaviors in the female rat (1977) Horm Behav, 8 (1), pp. 40-51Pleim, E.T., Brown, T.J., MacLusky, N.J., Etgen, A.M., Barfield, R.J., Dilute estradiol implants and progestin receptor induction in the ventromedial nucleus of the hypothalamus: correlation with receptive behavior in female rats (1989) Endocrinology, 124 (4), pp. 1807-1812Auger, A.P., Ligand-independent activation of progestin receptors: relevance for female sexual behaviour (2001) Reproduction, 122 (6), pp. 847-855Flanagan-Cato, L.M., Calizo, L.H., Daniels, D., The synaptic organization of VMH neurons that mediate the effects of estrogen on sexual behavior (2001) Horm Behav, 40 (2), pp. 178-182Witcher, J.A., Freeman, M.E., The proestrus surge of prolactin enhances sexual receptivity in the rat (1985) Biol Reprod, 32 (4), pp. 834-83

Vagotomy Ameliorates Islet Morphofunction And Body Metabolic Homeostasis In Msg-obese Rats.

The parasympathetic nervous system is important for β-cell secretion and mass regulation. Here, we characterized involvement of the vagus nerve in pancreatic β-cell morphofunctional regulation and body nutrient homeostasis in 90-day-old monosodium glutamate (MSG)-obese rats. Male newborn Wistar rats received MSG (4 g/kg body weight) or saline [control (CTL) group] during the first 5 days of life. At 30 days of age, both groups of rats were submitted to sham-surgery (CTL and MSG groups) or subdiaphragmatic vagotomy (Cvag and Mvag groups). The 90-day-old MSG rats presented obesity, hyperinsulinemia, insulin resistance, and hypertriglyceridemia. Their pancreatic islets hypersecreted insulin in response to glucose but did not increase insulin release upon carbachol (Cch) stimulus, despite a higher intracellular Ca2+ mobilization. Furthermore, while the pancreas weight was 34% lower in MSG rats, no alteration in islet and β-cell mass was observed. However, in the MSG pancreas, increases of 51% and 55% were observed in the total islet and β-cell area/pancreas section, respectively. Also, the β-cell number per β-cell area was 19% higher in MSG rat pancreas than in CTL pancreas. Vagotomy prevented obesity, reducing 25% of body fat stores and ameliorated glucose homeostasis in Mvag rats. Mvag islets demonstrated partially reduced insulin secretion in response to 11.1 mM glucose and presented normalization of Cch-induced Ca2+ mobilization and insulin release. All morphometric parameters were similar among Mvag and CTL rat pancreases. Therefore, the higher insulin release in MSG rats was associated with greater β-cell/islet numbers and not due to hypertrophy. Vagotomy improved whole body nutrient homeostasis and endocrine pancreatic morphofunction in Mvag rats

Early onset of obesity induces reproductive deficits in female rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The incidence of obesity is increasing rapidly all over the world and results in numerous health detriments, including disruptions in reproduction. However, the mechanisms by which excess body fat interferes with reproductive functions are still not fully understood. After weaning, female rats were treated with a cafeteria diet or a chow diet (control group). Biometric and metabolic parameters were evaluated in adulthood. Reproductive parameters, including estradiol, progesterone, LH and prolactin during the proestrus afternoon, sexual behavior, ovulation rates and histological analysis of ovaries were also evaluated. Cafeteria diet was able to induce obesity in female rats by increasing body and fat pad weight, which resulted in increased levels of triglycerides, total cholesterol, LDL and induced insulin resistance. The cafeteria diet also negatively affected female reproduction by reducing the number of oocytes and preantral follicles, as well as the thickness of the follicular layer. Obese females did not show preovulatory progesterone and LH surges, though plasma estradiol and prolactin showed preovulatory surges similar to control rats. Nevertheless, sexual receptiveness was not altered by cafeteria diet. Taken together, our results suggest that the cafeteria diet administered from weaning age was able to induce obesity and reduce the reproductive capability in adult female rats, indicating that this obesity model can be used to better understand the mechanisms underlying reproductive dysfunction in obese subjects. (C) 2012 Elsevier Inc. All rights reserved.105511041111Fundacao Araucaria de Apoio ao Desenvolvimento Cientifico e Tecnologico do Estado do ParanaSecretaria de CienciaTecnologia e Ensino Superior do Estado do ParanaConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Maternal Roux-en-Y gastric bypass impairs insulin action and endocrine pancreatic function in male F1 offspring

Purpose: Obesity is predominant in women of reproductive age. Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure that is performed in obese women for weight loss and metabolic improvement. However, some studies suggest that this procedure negatively affects offspring. Herein, using Western diet (WD)-obese female rats, we investigated the effects of maternal RYGB on postnatal body development, glucose tolerance, insulin secretion and action in their adult male F1 offspring. Methods: Female Wistar rats consumed a Western diet (WD) for 18 weeks, before being submitted to RYGB (WD-RYGB) or SHAM (WD-SHAM) operations. After 5 weeks, WD-RYGB and WD-SHAM females were mated with control male breeders, and the F1 offspring were identified as: WD-RYGB-F1 and WD-SHAM-F1. Results: The male F1 offspring of WD-RYGB dams exhibited decreased BW, but enhanced total nasoanal length gain. At 120 days of age, WD-RYGB-F1 rats displayed normal fasting glycemia and glucose tolerance but demonstrated reduced insulinemia and higher glucose disappearance after insulin stimulus. In addition, these rodents presented insulin resistance in the gastrocnemius muscle and retroperitoneal fat, as judged by lower Akt phosphorylation after insulin administration, but an increase in this protein in the liver. Finally, the islets from WD-RYGB-F1 rats secreted less insulin in response to glucose and displayed increased β-cell area and mass. Conclusions: RYGB in WD dams negatively affected their F1 offspring, leading to catch-up growth, insulin resistance in skeletal muscle and white fat, and β-cell dysfunction. Therefore, our data are the first to demonstrate that the RYGB in female rats may aggravate the metabolic imprinting induced by maternal WD consumption, in their male F1 descendants. However, since we only used male F1 rats, further studies are necessary to demonstrate if such effect may also occur in female F1 offspring from dams that underwent RYGB operation.5931067107

Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis

FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQThe exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In t85250258FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ2013/26740-0, 2014/01717-9, 2015/12611-0449794/2014-8The authors also thank Marise Carnelossi for excellent technical as-sistance and Karin Hoch Fehlauer Ale for English editin