Reproductive Tissues Maintain Insulin Sensitivity in Diet-Induced Obesity

Wu, Sheng; DiVall, Sara A.; Wondisford, Fredric E.; Wolfe, Andrew

doi:10.2337/db11-0956

Cited by 57 publications

(56 citation statements)

References 46 publications

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“…2). Studies in mice have revealed that liver and muscle cells exhibit IR during continuous HI, whereas insulin receptors in pituitary and ovarian cells stay sensitive, an adaptation that increases pituitary hormone secretion and ovarian androgen production [48]. This observation has been used as a model to explain the insulinemic contribution to advanced androgen production and progress to PCOS in women.…”

Section: Excess Insulin Has Multiple Effectsmentioning

confidence: 99%

Development of Obesity and Polycystic Ovary Syndrome in Adolescents

Vilmann¹,

Thisted²,

Baker³

et al. 2012

Horm Res Paediatr

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Obesity in adolescents is prevalent worldwide. Polycystic ovary syndrome (PCOS) is often associated with obesity in women, and it has serious metabolic and reproductive health implications. Although PCOS does not become clinically visible until early adolescence, its origins are likely much earlier. Therefore, we reviewed the recent literature regarding the mechanisms linking the development of PCOS and obesity in adolescent girls. We found that excess abdominal adipose tissue (AT) initiates metabolic and endocrine aberrations that are central in the progression of PCOS. As an example, abdominal AT impairs insulin action, which interacts with the progression of hyperandrogenism. In addition, excessive androgen levels lead to impaired glucose uptake, which also contributes to insulin resistance, which again increases the deposition of visceral fat. The body composition is influenced by testosterone, which decreases subcutaneous fat lipolysis and influences adipocyte distribution. These mechanisms may explain why PCOS girls have an increased visceral adipose mass independent of body mass index. Therefore, first-line treatment in adolescent PCOS is often lifestyle intervention to prevent the damaging effects of obesity. Pharmacological treatment of adolescent PCOS is not standardized because the long-term effects in adolescents have not yet been evaluated; therefore, drugs should be prescribed cautiously. Although the complex metabolic interrelationships between obesity and PCOS have yet to be fully understood, the co-occurrence of these conditions in adolescent girls tends to increase the severity of the negative health consequences of each condition.

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Section: Excess Insulin Has Multiple Effectsmentioning

confidence: 99%

Development of Obesity and Polycystic Ovary Syndrome in Adolescents

Vilmann¹,

Thisted²,

Baker³

et al. 2012

Horm Res Paediatr

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“…Prior studies by Akamine et al (2) and Nteeba et al (39) established that long exposure to high-fat diet in both rats and mice can lead to a similar reduction in PI3K and Akt phosphorylation in whole ovarian tissue, as seen in the current study compared with lean controls. Results from the present study demonstrate that insulin signaling may be affected by obesity; however, additional studies leveraging insulin challenges or hyperinsulinemic euglycemic clamps are warranted to confirm whether ovaries are insulin resistant in this model (2,66). Studies using primary granulosa cell cultures are also needed to test whether the decrease in PI3K and p-Akt leads to this upregulation of Egr-1.…”

Section: Discussionmentioning

confidence: 99%

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

Ruebel

Shankar

Gaddy

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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A. Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1. Am J Physiol Endocrinol Metab 311: E269 -E277, 2016. First published June 7, 2016 doi:10.1152/ajpendo.00524.2015.-Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a proinflammatory gene signature and upregulation of Egr-1 protein in ovaries from obese (OB; n ϭ 7) compared with lean (LN; n ϭ 10) female Sprague-Dawley rats during the peri-implantation period at 4.5 days postcoitus (dpc). Obesity was induced by overfeeding (40% excess calories for 28 days) via total enteral nutrition prior to mating. OB dams had higher body weight (P Ͻ 0.001), greater fat mass (P Ͻ 0.001), and reduced lean mass (P Ͻ 0.05) and developed metabolic dysfunction with elevated serum lipids, insulin, leptin, and CCL2 (P Ͻ 0.05) compared with LN dams. Microarray analyses identified 284 differentially expressed genes between ovaries from LN vs. OB dams (Ϯ1.3 fold, P Ͻ 0.05). RT-qPCR confirmed a decrease in expression of glucose transporters GLUT4 and GLUT9 and elevation of proinflammatory genes, including CCL2, CXCL10, CXCL11, CCR2, CXCR1, and TNF␣ in ovaries from OB compared with LN (P Ͻ 0.05). Protein levels of PI3K and phosphorylated Akt were significantly decreased (P Ͻ 0.05), whereas nuclear levels of Egr-1 (P Ͻ 0.05) were increased in OB compared with LN ovaries. Moreover, Egr-1 was localized to granulosa cells, with the highest expression in cumulus cells of preovulatory follicles. mRNA expression of VCAN, AURKB, and PLAT (P Ͻ 0.05) correlated with %visceral fat weight (r ϭ 0.51, Ϫ0.77, and Ϫ0.57, respectively, P Յ 0.05), suggesting alterations in ovarian function with obesity. In summary, maternal obesity led to an upregulation of inflammatory genes and Egr-1 expression in peri-implantation ovarian tissue and a concurrent downregulation of GLUTs and Akt and PI3K protein levels.early growth response factor 1; gene expression; inflammation; obesity; reproduction IN THE US, 60% OF WOMEN OF REPRODUCTIVE AGE are either overweight or obese, which predisposes them to higher risk of infertility and pregnancy complications (12,21,57,59,60) and potentially leads to adverse effects on offspring development. Higher adiposity leads to hormonal dysregulation, decreased primordial follicle numbers at the initiation of follicular development, lower ovulation rates, a reduced number of cleaved blastocysts developing to eight cell stage and reduced implantation rates, and ultimately impaired reproductive function (11,16,17,22,33,35,61). Similarly, in experimental models, obesity leads to decreased primordial and preovulatory follicle numbers, increased follicular atresia and changes in steroidogenesis via decreased steroidogenic acute regulatory protein, and increased Cyp11a1 protein content in ovarian tissue (7,16,23,37,38,53,61). Evidence of lipid accumulation, endoplasmic reticulum stress, and oxidative stress in ova...

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“…However, as fertility and corpora lutea numbers were incompletely rescued by pituitary insulin receptor deletion, obesity may have effects at other levels of the reproductive axis. In this regard, the ovary also remains insulin-sensitive in the obese state, and deletion of insulin receptors from ovarian theca interstitial cells also partially rescues obesity-induced infertility (Wu et al, 2013, 2012). The effect of obesity on GnRH neuronal function remains to be investigated.…”

Section: Adult Treatment Models For the Study Of Pcosmentioning

confidence: 99%

Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: Insight from animal models

Roland¹,

Moenter²

2014

Frontiers in Neuroendocrinology

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Polycystic ovary syndrome (PCOS) is a common endocrinopathy with elusive origins. A clinically heterogeneous disorder, PCOS is likely to have multiple etiologies comprised of both genetic and environmental factors. Reproductive neuroendocrine dysfunction involving increased frequency and amplitude of gonadotropin-releasing hormone (GnRH) release, as reflected by pulsatile luteinizing hormone (LH) secretion, is an important pathophysiologic component in PCOS. Whether this defect is primary or secondary to other changes in PCOS is unclear, but it contributes significantly to ongoing reproductive dysfunction. This review highlights recent work in animal models, with a particular emphasis on the mouse, demonstrating the ability of pre- and postnatal steroidal and metabolic factors to drive changes in GnRH/LH pulsatility and GnRH neuron function consistent with the observed abnormalities in PCOS. This work has begun to elucidate how a complex interplay of ovarian, metabolic, and neuroendocrine factors culminates in this syndrome.

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Reproductive Tissues Maintain Insulin Sensitivity in Diet-Induced Obesity

Cited by 57 publications

References 46 publications

Development of Obesity and Polycystic Ovary Syndrome in Adolescents

Development of Obesity and Polycystic Ovary Syndrome in Adolescents

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: Insight from animal models

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