Leveraging inter-individual transcriptional correlation structure to infer discrete signaling mechanisms across metabolic tissues.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

Loss of CTRP10 results in female obesity with preserved metabolic health.

Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologous in humans also show sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.

Feeding neurons integrate metabolic and reproductive states in mice.

Balance between metabolic and reproductive processes is important for survival, particularly in mammals that gestate their young. How the nervous system coordinates this balance is an active area of study. Herein, we demonstrate that somatostatin (SST) neurons of the tuberal hypothalamus alter feeding in a manner sensitive to metabolic and reproductive states in mice. Whereas chemogenetic activation of SST neurons increased food intake across sexes, ablation decreased food intake only in female mice during proestrus. This ablation effect was only apparent in animals with low body mass. Fat transplantation and bioinformatics analysis of SST neuronal transcriptomes revealed white adipose as a key modulator of these effects. These studies indicate that SST hypothalamic neurons integrate metabolic and reproductive cues by responding to varying levels of circulating estrogens to modulate feeding differentially based on energy stores. Thus, gonadal steroid modulation of neuronal circuits can be context dependent and gated by metabolic status.

Feeding Neurons Integrate Metabolic and Reproductive States in Mice.

Trade-offs between metabolic and reproductive processes are important for survival, particularly in mammals that gestate their young. Puberty and reproduction, as energetically taxing life stages, are often gated by metabolic availability in animals with ovaries. How the nervous system coordinates these trade-offs is an active area of study. We identify somatostatin neurons of the tuberal nucleus (TNSST) as a node of the feeding circuit that alters feeding in a manner sensitive to metabolic and reproductive states in mice. Whereas chemogenetic activation of TNSST neurons increased food intake across sexes, selective ablation decreased food intake only in female mice during proestrus. Interestingly, this ablation effect was only apparent in animals with a low body mass. Fat transplantation and bioinformatics analysis of TNSST neuronal transcriptomes revealed white adipose as a key modulator of the effects of TNSST neurons on food intake. Together, these studies point to a mechanism whereby TNSST hypothalamic neurons modulate feeding by responding to varying levels of circulating estrogens differentially based on energy stores. This research provides insight into how neural circuits integrate reproductive and metabolic signals, and illustrates how gonadal steroid modulation of neuronal circuits can be context-dependent and gated by metabolic status.

Dysregulated systemic metabolism in a Down syndrome mouse model.

OBJECTIVE: Trisomy 21 is one of the most complex genetic perturbations compatible with postnatal survival. Dosage imbalance arising from the triplication of genes on human chromosome 21 (Hsa21) affects multiple organ systems. Much of Down syndrome (DS) research, however, has focused on addressing how aneuploidy dysregulates CNS function leading to cognitive deficit. Although obesity, diabetes, and associated sequelae such as fatty liver and dyslipidemia are well documented in the DS population, only limited studies have been conducted to determine how gene dosage imbalance affects whole-body metabolism. Here, we conduct a comprehensive and systematic analysis of key metabolic parameters across different physiological states in the Ts65Dn trisomic mouse model of DS. METHODS: Ts65Dn mice and euploid littermates were subjected to comprehensive metabolic phenotyping under basal (chow-fed) state and the pathophysiological state of obesity induced by a high-fat diet (HFD). RNA sequencing of liver, skeletal muscle, and two major fat depots were conducted to determine the impact of aneuploidy on tissue transcriptome. Pathway enrichments, gene-centrality, and key driver estimates were performed to provide insights into tissue autonomous and non-autonomous mechanisms contributing to the dysregulation of systemic metabolism. RESULTS: Under the basal state, chow-fed Ts65Dn mice of both sexes had elevated locomotor activity and energy expenditure, reduced fasting serum cholesterol levels, and mild glucose intolerance. Sexually dimorphic deterioration in metabolic homeostasis became apparent when mice were challenged with a high-fat diet. While obese Ts65Dn mice of both sexes exhibited dyslipidemia, male mice also showed impaired systemic insulin sensitivity, reduced mitochondrial activity, and elevated fibrotic and inflammatory gene signatures in the liver and adipose tissue. Systems-level analysis highlighted conserved pathways and potential endocrine drivers of adipose-liver crosstalk that contribute to dysregulated glucose and lipid metabolism. CONCLUSIONS: A combined alteration in the expression of trisomic and disomic genes in peripheral tissues contribute to metabolic dysregulations in Ts65Dn mice. These data lay the groundwork for understanding the impact of aneuploidy on in vivo metabolism.

Lipopolysaccharide-induced chronic inflammation increases female serum gonadotropins and shifts the pituitary transcriptomic landscape.

Introduction: Female reproductive function depends on a choreographed sequence of hormonal secretion and action, where specific stresses such as inflammation exert profound disruptions. Specifically, acute LPS-induced inflammation inhibits gonadotropin production and secretion from the pituitary, thereby impacting the downstream production of sex hormones. These outcomes have only been observed in acute inflammatory stress and little is known about the mechanisms by which chronic inflammation affects reproduction. In this study we seek to understand the chronic effects of LPS on pituitary function and consequent luteinizing and follicle stimulating hormone secretion. Methods: A chronic inflammatory state was induced in female mice by twice weekly injections with LPS over 6 weeks. Serum gonadotropins were measured and bulk RNAseq was performed on the pituitaries from these mice, along with basic measurements of reproductive biology. Results: Surprisingly, serum luteinizing and follicle stimulating hormone was not inhibited and instead we found it was increased with repeated LPS treatments. Discussion: Analysis of bulk RNA-sequencing of murine pituitary revealed paracrine activation of TGFß pathways as a potential mechanism regulating FSH secretion in response to chronic LPS. These results provide a framework with which to begin dissecting the impacts of chronic inflammation on reproductive physiology.

Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer.

An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc, a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention.

Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones.

Skeletal muscle plays an integral role in coordinating physiological homeostasis, where signaling to other tissues via myokines allows for coordination of complex processes. Here, we aimed to leverage natural genetic correlation structure of gene expression both within and across tissues to understand how muscle interacts with metabolic tissues. Specifically, we performed a survey of genetic correlations focused on myokine gene regulation, muscle cell composition, cross-tissue signaling, and interactions with genetic sex in humans. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little relative differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion; in particular, with estradiol. These sex- and hormone-specific effects were consistent across key metabolic tissues: liver, pancreas, hypothalamus, intestine, heart, visceral, and subcutaneous adipose tissue. To characterize the role of estradiol receptor signaling on myokine expression, we generated male and female mice which lack estrogen receptor α specifically in skeletal muscle (MERKO) and integrated with human data. These analyses highlighted potential mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes. Several other putative sex-dependent mechanisms of myokine signaling were uncovered, such as muscle-derived tumor necrosis factor alpha (TNFA) enriched for stronger inflammatory signaling in females compared to males and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide a population genetics framework for inferring muscle signaling to metabolic tissues in humans. We further highlight sex and estradiol receptor signaling as critical variables when assaying myokine functions and how changes in cell composition are predicted to impact other metabolic organs.

The muscles that are responsible for voluntary movements such as exercise are called skeletal muscles. These muscles secrete proteins called myokines, which play roles in a variety of processes by interacting with other tissues. Essentially, myokines allow skeletal muscles to communicate with organs such as the kidneys, the liver or the brain, which is essential for the body to keep its metabolic balance. Some of the process myokines are involved include inflammation, cancer, the changes brought about by exercise, and even cognition. Despite the clear relevance of myokines to so many physiological outcomes, the way these proteins are regulated and their effects are not well understood. Genetic sex ­ specified by sex chromosomes in mammals ­ contributes to critical aspects of physiology. Specifically, many of the metabolic traits impacted by myokines show striking differences arising from hormonal or genetic interactions depending on the genetic sex of the subject being studied. It is therefore important to consider genetic sex when studying the effects of myokines on the body. Velez, Van et al. wanted to gain a better understanding of how skeletal muscles interact with metabolic tissues such as pancreas, liver and brain, taking genetic sex into consideration. To do this they surveyed human datasets for the correlations between the activity of genes that code for myokines, the composition of muscle cells, the signaling between muscles and metabolic tissues and genetic sex. Their results showed that, genetic sex and sex hormones predicted most of the effects of skeletal muscle on other tissues. For example, myokines from muscle were predicted to be more impactful on liver or pancreas, depending on whether individuals were male or female, respectively. The results of Velez, Van et al. illustrate the importance of considering the effects of genetic sex and sexual hormones when studying metabolism. In the future, these results will allow other researchers to design sex-specific experiments to be able to gather more accurate information about the mechanisms of myokine signaling.

Inflammation and reproductive function in women with polycystic ovary syndrome†.

Polycystic ovary syndrome (PCOS) is one of the most frequent endocrinopathies, affecting 5-10% of women of reproductive age, and is characterized by the presence of ovarian cysts, oligo, or anovulation, and clinical or biochemical hyperandrogenism. Metabolic abnormalities such as hyperinsulinemia, insulin resistance, cardiovascular complications, dyslipidemia, and obesity are frequently present in PCOS women. Several key pathogenic pathways overlap between these metabolic abnormalities, notably chronic inflammation. The observation that this mechanism was shared led to the hypothesis that a chronic inflammatory state could contribute to the pathogenesis of PCOS. Moreover, while physiological inflammation is an essential feature of reproductive events such as ovulation, menstruation, implantation, and labor at term, the establishment of chronic inflammation may be a pivotal feature of the observed reproductive dysfunctions in PCOS women. Taken together, the present work aims to review the available evidence about inflammatory mediators and related mechanisms in women with PCOS, with an emphasis on reproductive function.

Prenatal androgen excess alters the uterine peroxisome proliferator-activated receptor (PPAR) system.

It is known that androgen excess induces changes in fetal programming that affect several physiological pathways. Peroxisome proliferator-activated receptors (PPARs) α, δ and γ are key mediators of female reproductive functions, in particular in uterine tissues. Thus, we aimed to study the effect of prenatal hyperandrogenisation on the uterine PPAR system. Rats were treated with 2mg testosterone from Day 16 to 19 of pregnancy. Female offspring (PH group) were followed until 90 days of life, when they were killed. The PH group exhibited an anovulatory phenotype. We quantified uterine mRNA levels of PPARα (Ppara ), PPARδ (Ppard ), PPARγ (Pparg ), their regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a ) and nuclear receptor co-repressor 1 (Ncor1 ) and cyclo-oxygenase (COX)-2 (Ptgs2 ), and assessed the lipid peroxidation (LP) index and levels of glutathione (GSH) and prostaglandin (PG) E2 . The PH group showed decreased levels of all uterine PPAR isoforms compared with the control group. In addition, PGE2 and Ptgs2 levels were increased in the PH group, which led to a uterine proinflammatory environment, as was LP, which led to a pro-oxidant status that GSH was not able to compensate for. These results suggest that prenatal exposure to androgen excess has a fetal programming effect that affects the gene expression of PPAR isoforms, and creates a misbalanced oxidant-antioxidant state and a proinflammatory status.

Treatment with the synthetic PPARG ligand pioglitazone ameliorates early ovarian alterations induced by dehydroepiandrosterone in prepubertal rats.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear factor that may act on the early development of ovarian follicles and on follicular steroidogenesis. However, the exact mechanism of PPARG action remains unknown. We have previously found that androgen excess alters early ovarian function and the PPARG system. The aim of the present study was to evaluate whether PPARG activation (using the synthetic ligand pioglitazone (PGZ)) ameliorates the alterations in early ovarian function induced by androgen excess. METHODS: Female prepubertal rats were treated with equine chorionic gonadotropin (eCG) to induce folliculogenesis, together with dehydroepiandrosterone (DHEA) to induce hyperandrogenism and/or PGZ to evaluate PPARG activation. We assessed i) very early ovarian folliculogenesis, ii) PPARG activation, iii) ovarian steroidogenic enzymes, iv) the estradiol/testosterone ratio, v) the ovarian inflammatory status and vi) oxidative stress. RESULTS: PGZ prevented the inactivation of ovarian PPARG induced by androgen excess by increasing PPARG itself and the gene expression of PPARG-coactivator 1 alpha (PGC1A), and by decreasing the gene expression of nuclear co-repressor (NCOR). PGZ also prevented the altered ovarian steroidogenesis, pro-inflammatory status and oxidative stress induced by androgen excess. CONCLUSIONS: Our findings suggest that PPARG activation plays important roles in modulating early ovarian function, and highlight the importance of understanding the role(s) of PPARG activation in the ovary, and the possible involvement in the treatment of ovarian pathologies, and/or the impact in regulating/improving fertility.

Effect of hyperandrogenism on ovarian function.

The objective of this work was to study the ovarian function when follicular development is induced during a hyperandrogenic condition. Female rats were injected with either equine chorionic gonadotropin (eCG group) to induce folliculogenesis or eCG together with DHEA to induce folliculogenesis in a hyperandrogenic condition (eCG+HA group). The control group was injected with vehicle. Ovarian mRNA levels of the peroxisome proliferator-activated receptor gamma (PPARγ) co-activator PGC1α, the PPARγ co-repressor NCoR, the main enzymes involved in the ovarian steroidogenesis (CYP17, 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 17ß-HSD, and CYP19A), and cyclooxygenase 2 (COX2) were evaluated only by real-time PCR. COX2 was evaluated by both real-time PCR and western blot. Serum steroid hormones and both the oxidative and inflammatory statuses were also quantified. We found that eCG-induced folliculogenesis induced increased mRNA levels of PGC1α and decreased those of NCoR when compared with controls. In addition, we found an increase in serum estradiol (E2) levels and enhanced mRNA expression of CYP19A. A pro-inflammatory status and a pro-oxidant status were also established. When folliculogenesis was induced in a hyperandrogenic condition, the mRNA levels of the PPARγ co-repressor NCoR remained higher than in controls and the pro-inflammatory and pro-oxidant statuses were enhanced. In addition, the enzymes involved in ovarian steroidogenesis were altered leading to the accumulation of testosterone and an unfavorable E2/testosterone ratio. These alterations led to abnormal follicular development.

Prenatal hyperandrogenism and lipid profile during different age stages: an experimental study.

OBJECTIVE: The present study investigates the effect of prenatal hyperandrogenization on lipid metabolism and oxidant/antioxidant balance. DESIGN: Experimental study. SETTING: Research institute. ANIMAL(S): Pregnant Sprague Dawley rats were subcutaneously injected with 2 mg free T between days 16 and 19 of pregnancy, and controls (C) received vehicle (0.1 mL of sesame oil). Prenatally hyperandrogenized female offspring (T2) had a condition that resembles polycystic ovary (PCO). Animals were weighed and killed at 21 and 60 days of age (N = 15 rats/group). INTERVENTION(S): Ovarian tissue and truncal blood were obtained from the C and T2 groups. MAIN OUTCOME MEASURE(S): Circulating lipid profile (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL] cholesterol, and triglycerides) was quantified by colorimetric-enzymatic methods. Ovarian oxidative stress was evaluated by quantifying lipid peroxidation and glutathione content by spectofotometric assays. Ovarian fat content was evaluated by Red Oil staining and ovarian messenger RNA (mRNA) expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) by real-time polymerase chain reaction (PCR). RESULT(S): At 60 days of age, 100% of group C rats and 20% of group T2 rats ovulated. At 21 days of age the T2 rats displayed lower body weight than C rats; however, at 60 days of age T2 and C rats showed similar body weights. The lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) was altered in the anovulatory and ovulatory phenotype of the T2 group, but the levels were higher in the anovulatory phenotype. Lipid peroxidation of rats at 21 and 60 days of age from T2 was similar to C but the antioxidant glutathione level was decreased in 21-day-old rats compared with C rats. The lipid content of ovarian tissue, determined by Red Oil staining, was higher in the T2 than in the C group. The mRNA expression of ovarian PPAR-γ, quantified by real time PCR, decreased in anovulatory rats at 60 days of age from T2 compared to C rats. CONCLUSION(S): Our findings reveal the importance of evaluating the complete lipid profile, especially at early stages of life after the prenatal hyperandrogenism condition. In addition, we demonstrated that the antioxidant-reduced glutathione would represent a good marker of oxidative stress as it is altered before lipid peroxidation. Prenatal hyperandrogenization also alters the gene expression of PPAR-γ in rats. Here we demonstrated for the first time that abnormalities in PPAR-γ and lipid profile were higher in rats showing an anovulatory phenotype than those displaying an ovulatory phenotype.

[The role of prenatal hyperandrogenism on lipid metabolism during adult life in a rat model]. / Hiperandrogenización prenatal en ratas y el metabolismo lipídico en la vida adulta.

Polycystic ovary syndrome (PCOS) is one of the commonest endocrine diseases that affect women in their reproductive ages; however, the etiology of the syndrome remains unknown. A hypothesis proposes that during gestation increased exposure of androgen would induce fetal programming that may increase the risk of PCOS development during the adult life. By means of a prenatally hyperandrogenized (HA) rat model we demonstrated the importance of determining the lipid profile at early ages. HA induced two different phenotypes: ovulatory and anovulatory PCOS. HA did not modify total cholesterol but decreased HDL cholesterol and increased both LDL and tryglicerides (TG) when compared with controls. Both, the ratio total cholesterol: HDL (marker of cardiovascular risk) and TG:HDL (marker of metabolic syndrome) were increased in the HA group with respect to controls. In addition, these abnormalities were stronger in the anovulatory than ovulatory phenotype. Our results point out the need to find early markers of PCOS in girls or adolescents with increased risk to develop PCOS (as in daughters of women with PCOS).

Hiperandrogenización prenatal en ratas y el metabolismo lipídico en la vida adulta / The role of prenatal hyperandrogenism on lipid metabolism during adult life in a rat model

El síndrome del ovario poliquístico (PCOS) es una afección de alta incidencia en mujeres en edad fértil. Si bien la etiología de la enfermedad se desconoce, se cree que la exposición a andrógenos durante la vida intrauterina generaría reprogramación fetal afectando vías endocrinas y metabólicas que, junto a alteraciones génicas y ambientales, inducirían la aparición de PCOS en etapas muy tempranas de la vida. Es por ello que se buscan marcadores tempranos del desarrollo de PCOS. Utilizando un modelo murino de hiperandrogenización prenatal (HA) recreamos dos fenotipos de PCOS: ovulatorio y anovulatorio. La HA no alteró el colesterol circulante pero disminuyó el colesterol HDL y aumentó el LDL y los triglicéridos (TG) con respecto a los controles. La relación colesterol total/HDL como marcador de riesgo cardiovascular y la relación TG/HDL se vieron incrementadas con respecto a los controles, resultando mayor en el grupo PCOS anovulatorio. El presente trabajo demuestra la importancia de la determinación del perfil lipídico a edades tempranas en poblaciones de riesgo (como es el caso de hijas de madres con PCOS).

Polycystic ovary syndrome (PCOS) is one of the commonest endocrine diseases that affect women in their reproductive ages; however, the etiology of the syndrome remains unknown. A hypothesis proposes that during gestation increased exposure of androgen would induce fetal programming that may increase the risk of PCOS development during the adult life. By means of a prenatally hyperandrogenized (HA) rat model we demonstrated the importance of determining the lipid profile at early ages. HA induced two different phenotypes: ovulatory and anovulatory PCOS. HA did not modify total cholesterol but decreased HDL cholesterol and increased both LDL and tryglicerides (TG) when compared with controls. Both, the ratio total cholesterol: HDL (marker of cardiovascular risk) and TG:HDL (marker of metabolic syndrome) were increased in the HA group with respect to controls. In addition, these abnormalities were stronger in the anovulatory than ovulatory phenotype. Our results point out the need to find early markers of PCOS in girls or adolescents with increased risk to develop PCOS (as in daughters of women with PCOS).

Hiperandrogenización prenatal en ratas y el metabolismo lipídico en la vida adulta / The role of prenatal hyperandrogenism on lipid metabolism during adult life in a rat model

El síndrome del ovario poliquístico (PCOS) es una afección de alta incidencia en mujeres en edad fértil. Si bien la etiología de la enfermedad se desconoce, se cree que la exposición a andrógenos durante la vida intrauterina generaría reprogramación fetal afectando vías endocrinas y metabólicas que, junto a alteraciones génicas y ambientales, inducirían la aparición de PCOS en etapas muy tempranas de la vida. Es por ello que se buscan marcadores tempranos del desarrollo de PCOS. Utilizando un modelo murino de hiperandrogenización prenatal (HA) recreamos dos fenotipos de PCOS: ovulatorio y anovulatorio. La HA no alteró el colesterol circulante pero disminuyó el colesterol HDL y aumentó el LDL y los triglicéridos (TG) con respecto a los controles. La relación colesterol total/HDL como marcador de riesgo cardiovascular y la relación TG/HDL se vieron incrementadas con respecto a los controles, resultando mayor en el grupo PCOS anovulatorio. El presente trabajo demuestra la importancia de la determinación del perfil lipídico a edades tempranas en poblaciones de riesgo (como es el caso de hijas de madres con PCOS).(AU)

Polycystic ovary syndrome (PCOS) is one of the commonest endocrine diseases that affect women in their reproductive ages; however, the etiology of the syndrome remains unknown. A hypothesis proposes that during gestation increased exposure of androgen would induce fetal programming that may increase the risk of PCOS development during the adult life. By means of a prenatally hyperandrogenized (HA) rat model we demonstrated the importance of determining the lipid profile at early ages. HA induced two different phenotypes: ovulatory and anovulatory PCOS. HA did not modify total cholesterol but decreased HDL cholesterol and increased both LDL and tryglicerides (TG) when compared with controls. Both, the ratio total cholesterol: HDL (marker of cardiovascular risk) and TG:HDL (marker of metabolic syndrome) were increased in the HA group with respect to controls. In addition, these abnormalities were stronger in the anovulatory than ovulatory phenotype. Our results point out the need to find early markers of PCOS in girls or adolescents with increased risk to develop PCOS (as in daughters of women with PCOS).(AU)