Modulation of transforming growth factor-β/follistatin signaling and white adipose browning: therapeutic implications for obesity related disorders

Pervin, Shehla; Singh, Vineeta; Tucker, Alexandria; Collazo, Javier; Singh, Rajan

doi:10.1515/hmbci-2017-0036

Cited by 11 publications

(9 citation statements)

References 95 publications

(136 reference statements)

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“…Consistent with gestational origins of PCOSlike metabolic dysfunction, increased postnatal weight gain is associated with increased risk of PCOS in women [13], as well as T2D [138]. Interestingly, DNA methylation array analysis of visceral adipose identifies transforming growth factor beta (TGF-beta) signaling as the most significantly altered pathway in adult, T-exposed female monkeys [147], implicating an influential signaling pathway regulating adipocyte catabolism (brown or beige adipose, BAT) and adipocyte accumulation of lipid (white adipose, WAT) that may enable positive energy balance [148,149] favoring weight gain.…”

Section: Nonhuman Female Primatesmentioning

confidence: 99%

Hyperandrogenic origins of polycystic ovary syndrome – implications for pathophysiology and therapy

Abbott

Dumesic

Levine

2019

Expert Review of Endocrinology & Metabolism

106

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Introduction: Polycystic ovary syndrome (PCOS) diagnosis comprises combinations of female hyperandrogenism, menstrual irregularity and polycystic ovaries. While it is a familial and highly prevalent endocrine disorder, progress towards a cure is hindered by absence of a definitive pathogenic mechanism and lack of an animal model of naturally occurring PCOS. Areas covered: These include an overview of PCOS and its potential etiology, and an examination of insights gained into its pathogenic origins. Animal models derived from experimentally-induced hyperandrogenism during gestation, or from naturally-occurring PCOSlike traits, most reliably demonstrate reproductive, neuroendocrine and metabolic pathogenesis. Expert Commentary: Genetic studies, while identifying at least 17 PCOS risk genes, account for <10% of women with PCOS. A number of PCOS risk genes involve regulation of gonadotropin secretion or action, suggesting a reproductive neuroendocrine basis for PCOS pathogenesis. Consistent with this notion, a number of animal models employing fetal androgen excess demonstrate epigenetic induction of PCOS-like traits, including reproductive neuroendocrine and metabolic dysfunction. Monkey models are most comprehensive, while mouse models provide molecular insight, including identifying the androgen receptor, particularly in neurons, as mediating androgen-induced PCOS-like programming. Naturally-occurring female hyperandrogenism is also demonstrated in monkeys. Animal models are poised to delineate molecular gateways to PCOS pathogenesis.

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Section: Nonhuman Female Primatesmentioning

confidence: 99%

Hyperandrogenic origins of polycystic ovary syndrome – implications for pathophysiology and therapy

Abbott

Dumesic

Levine

2019

Expert Review of Endocrinology & Metabolism

106

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“…al) [21]. Follistatin was found to promote adipocyte differentiation, browning, and energy metabolism [22,23]. The identification and characterization of novel batokines may provide opportunities for therapeutic interventions in metabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

Fang

et al. 2019

Metabolism

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The thermogenic brown adipose tissue (BAT) has been proposed as a potential target to prevent or treat obesity and related metabolic diseases. BAT secretes adipokines to regulate the thermogenic program in an autocrine or paracrine manner. Follistatin-like 1 (FSTL1), a glycoprotein involved in adipogenesis and obesity, however, the function of FSTL1 in BAT thermogenesis and in the regulation of systemic energy homeostasis are not fully understood. Methods: Whole-body ablation Fstl1 heterozygous mice (Fstl1 +/−) and its littermates control were injected with CL316,243 to assess energy balance. A series of FSTL1 overexpression and knockdown experiments were carried out to evaluate its function in regulating thermogenic gene expression in brown adipocytes. Results: FSTL1 expression was induced upon BAT activation during cold challenge or β3-adrenergic activation. FSTL1 haploinsufficiency in mice led to reduced thermogenic gene expression, impaired BAT recruitment, and decreased heat production. FSTL1 cell-autonomously promoted the β3-adrenergic signaling, which was required to upregulate PPARγ and UCP1 in brown adipocytes. Furthermore, only glycosylated FSTL1 could be secreted from brown adipocytes to induce the β3-adrenergic activation. Conclusions: Our results suggest FSTL1 as a novel stimulator of the β-adrenergic signaling and BAT thermogenesis.

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“…Consistent with gestational origins of PCOSlike metabolic dysfunction, increased postnatal weight gain is associated with increased risk of PCOS in women [54], as well as T2D [64]. Interestingly, DNA methylation array analysis of visceral adipose identifies transforming growth factor beta (TGF-beta) signaling as the most significantly altered pathway in adult, T-exposed female monkeys [11], implicating an influential signaling pathway regulating adipocyte catabolism (brown or beige adipose, BAT) and adipocyte accumulation of lipid (white adipose, WAT) that potentially enables positive energy balance [75,76] favoring weight gain.…”

Section: Mechanistic Pcos Insight From Nonhuman Primate Models Of In Utero Female Hyperandrogenismmentioning

confidence: 99%

In utero Androgen Excess: A Developmental Commonality Preceding Polycystic Ovary Syndrome?

Abbott

Kraynak

Dumesic

et al. 2019

Frontiers of Hormone Research

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In utero androgen excess reliably induces polycystic ovary syndrome (PCOS)-like reproductive and metabolic traits in female monkeys, sheep, rats and mice. In humans, however, substantial technical and ethical constraints on fetal sampling have curtailed safe, pathogenic exploration during gestation. Evidence consistent with in utero origins for PCOS in humans has thus been slow to amass, but the balance now leans towards developmental fetal origins. Given that PCOS is familial and highly heritable, difficulty in discerning genetic contributions to PCOS pathogenesis is puzzling and, to date, accounts for <10% of PCOS presentations. Unaccounted heritability notwithstanding, molecular commonality in pathogenic mechanism is emerging, suggested by cooccurrence of replicated PCOS genetic variants and epigenetic alterations in DNA methylation at the same replicated, PCOS risk loci with bioinformatics-identified gene loci within monkey epigenetic alterations in DNA methylation array-determined gene networks from females exposed to testosterone (T) in utero. In addition, naturally occurring female hyperandrogenism in monkeys singles out females with PCOS-like reproductive and metabolic traits accompanied by somatic biomarkers of in utero T exposure. Such phenotypic and molecular convergence between highly related species, suggests not only dual genetic and epigenetic contributions to PCOS, as well as a developmental origin, but also common molecular pathogenesis extending beyond humans.

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Modulation of transforming growth factor-β/follistatin signaling and white adipose browning: therapeutic implications for obesity related disorders

Cited by 11 publications

References 95 publications

Hyperandrogenic origins of polycystic ovary syndrome – implications for pathophysiology and therapy

Hyperandrogenic origins of polycystic ovary syndrome – implications for pathophysiology and therapy

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

In utero Androgen Excess: A Developmental Commonality Preceding Polycystic Ovary Syndrome?

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