This paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single-gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.

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The human obesity gene map: the 2005 update.

This paper presents the eleventh update of the human obesity gene map, which incorporates published results up to the end of October 2004. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTLs) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2004, 173 human obesity cases due to single-gene mutations in 10 different genes have been reported, and 49 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 166 genes which, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 221. The number of human obesity QTLs derived from genome scans continues to grow, and we have now 204 QTLs for obesity-related phenotypes from 50 genome-wide scans. A total of 38 genomic regions harbor QTLs replicated among two to four studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably with 358 findings of positive associations with 113 candidate genes. Among them, 18 genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, >600 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful publications and genomic and other relevant sites can be found at http://obesitygene.pbrc.edu.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/oby.2005.50

The human obesity gene map: the 2004 update.

There is now a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in proinflammatory cytokines. The cytokines that have obtained the most attention are IL-1, IL-6, and TNF-alpha. The exact mechanisms by which estrogen interferes with cytokine activity are still incompletely known but may potentially include interactions of the ER with other transcription factors, modulation of nitric oxide activity, antioxidative effects, plasma membrane actions, and changes in immune cell function. Experimental and clinical studies strongly support a link between the increased state of proinflammatory cytokine activity and postmenopausal bone loss. Preliminary evidence suggests that these changes also might be relevant to vascular homeostasis and the development of atherosclerosis. Better knowledge of the mechanisms and the time course of these interactions may open new avenues for the prevention and treatment of some of the most prevalent and important disorders in postmenopausal women.

Changes in proinflammatory cytokine activity after menopause.

Although it has been known for many years that estrogen administration has deleterious effects on male fertility, data from transgenic mice deficient in estrogen receptors or aromatase point to an essential physiological role for estrogen in male fertility. This review summarizes the current knowledge on the localization of estrogen receptors and aromatase in the testis in an effort to understand the likely sites of estrogen action. The review also discusses the many studies that have used models employing the administration of estrogenic substances to show that male fertility is responsive to estrogen, thus providing a mechanism by which inappropriate exposure to estrogenic substances may cause adverse effects on spermatogenesis and male fertility. The reproductive phenotypes of mice deficient in estrogen receptors alpha and/or beta and aromatase are also compared to evaluate the physiological role of estrogen in male fertility. The review focuses on the effects of estrogen administration or deprivation, primarily in rodents, on the hypothalamo-pituitary-testis axis, testicular function (including Leydig cell, Sertoli cell, and germ cell development and function), and in the development and function of the efferent ductules and epididymis. The requirement for estrogen in normal male sexual behavior is also reviewed, along with the somewhat limited data on the fertility of men who lack either the capacity to produce or respond to estrogen. This review highlights the ability of exogenous estrogen exposure to perturb spermatogenesis and male fertility, as well as the emerging physiological role of estrogens in male fertility, suggesting that, in this local context, estrogenic substances should also be considered "male hormones."

Estrogen and spermatogenesis.

Over the last two decades, the incidence of obesity and associated metabolic syndrome diseases has risen dramatically, becoming a global health crisis Increased caloric intake and decreased physical activity are believed to represent the root causes of this dramatic rise However, recent findings highlight the possible involvement of environmental obesogens, xenobiotic chemicals that can disrupt the normal developmental and homeostatic controls over adipogenesis and energy balance Environmental estrogens, ie chemicals with estrogenic potential, have been reported to perturb adipogenic mechanisms using in vitro model systems, but other classes of endocrine-disrupting chemicals are now coming under scrutiny as well Organotins represent one class of widespread persistent organic pollutants with potent endocrine-disrupting properties in both invertebrates and vertebrates New data identify tributyltin chloride and triphenyltin chloride as nanomolar agonist ligands for retinoid X receptor (RXR alpha, RXR beta, and RXR gamma) and peroxisome proliferator-activated receptor gamma, nuclear receptors that play pivotal roles in lipid homeostasis and adipogenesis The environmental obesogen hypothesis predicts that inappropriate receptor activation by organotins will lead directly to adipocyte differentiation and a predisposition to obesity and/or will sensitize exposed individuals to obesity and related metabolic disorders under the influence of the typical high-calorie, high-fat Western diet The linking of organotin exposure to adipocyte differentiation and obesity opens an important new area of research into potential environmental influences on human health and disease

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Environmental Obesogens: Organotins and Endocrine Disruption via Nuclear Receptor Signaling

Targeted disruption of the receptor for glycoprotein hormone, FSH (FSH-R) causes a gene dose-related endocrine and gametogenic abnormality in female mice. The resulting FSH-R knockout (FORKO) mutants have disordered estrous cycles, ovulatory defects, and atrophic uterus. The heterozygous animals that initially show reduced fertility undergo early reproductive senescence and stop breeding altogether. Lack of FSH-R signaling in females causes severe ovarian underdevelopment producing chronic estrogen deficiency. This was accompanied by increases in serum testosterone levels. Ovarian aromatase gene transcription and translation are unaltered in the mutants. Early loss of estrogen in the null mutants leads to obesity and skeletal abnormalities that intensify with age producing (kyphosis), a hunchback appearance. Both these changes also become apparent in older heterozygous mice coincident with early reproductive senescence. The expression of nuclear estrogen receptor(s) a and b genes and the corresponding proteins in the ovary and uterus of FORKO mice appear to be intact. The loss of ovarian estrogen creates an imbalance in A and B forms of the progesterone receptor in the uterus of both heterozygotes and null mutants. Some of the changes we have documented here in FORKO mice are reminiscent of the ovarian dysfunction and other major symptoms that are usually associated with estrogen deficiency. In null mutants, estradiol-17b administration promptly induced uterine growth and reversed the accumulation of adipose tissue indicating that estrogen receptors are functional. Thus, the phenotypes evident in these genetically altered FSH-R mutants may provide an experimental system to explore the effects of estrogenic compounds on different targets including the ovary in a nonsurgical setting. (Endocrinology 141: 4295‐ 4308, 2000)

/pdf/estrogen-deficiency-obesity-and-skeletal-abnormalities-in-3m9hsnt3sn.pdf

Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice.

Sertoli cells express functional receptors for FSH, one of the two pituitary hormones that regulate spermatogenesis in mammals. We recently produced genetic mutant (FORKO) mice that lack FSH receptor, in order to examine the effects on testicular function and fertility. Mutant males exhibited weight loss of testis, epididymis, and seminal vesicle as well as low levels of testosterone. Except for reduced seminiferous tubular diameter, no gross changes were apparent upon histological examination. Analysis of testicular germ cells by flow cytometry revealed a significant increase in the percentage of 2C cells (spermatogonia and non-germ cells) and a significant decrease in the percentage of HC cells (elongated spermatids) of FORKO males. The absolute number of homogenization-resistant elongated spermatids was also significantly reduced in the mutant males. A 2-fold increase in c-kit-positive 2C cells was recorded in the mutant males. Elongated spermatids of FORKO males showed a dramatic increase in propidium iodide binding suggesting reduced nuclear compaction. The increase in size of the sperm head in mutants, as well as susceptibility to dithiothreitol-induced decondensation, suggests the inadequate condensation of sperm chromatin. Sperm chromatin structure assay, a technique that reflects DNA stability, revealed that sperm from FORKO males are susceptible to acid denaturation, indicating the poor quality of sperm. These data allow us to conclude that genetic disruption of FSH receptor signaling in the rodent induces major changes that might contribute to reduced fertility.

https://bioone.org/journals/biology-of-reproduction/volume-62/issue-5/biolreprod62.5.1146/Qualitative-and-Quantitative-Decline-in-Spermatogenesis-of-the-Follicle-Stimulating/10.1095/biolreprod62.5.1146.pdf

Qualitative and Quantitative Decline in Spermatogenesis of the Follicle-Stimulating Hormone Receptor Knockout (FORKO) Mouse

Activation of Extracellular-regulated Kinase Pathways in Ovarian Granulosa Cells by the Novel Growth Factor Type 1 Follicle-stimulating Hormone Receptor: ROLE IN HORMONE SIGNALING AND CELL PROLIFERATION

Germ cell transplantation, which offers promising new approaches for research and clinical applications, has focused interest on spermatogonia. This paper describes a procedure that permits the isolation of large quantities of viable spermatogonia. The immunomagnetic isolation procedure was applied to testicular cell suspensions from photoinhibited and photostimulated Djungarian hamsters, mice, and marmoset monkeys. The cells were incubated with a polyclonal rabbit anti-c-kit IgG, binding of which was characterized by immunohistochemical staining. For magnetic labeling, a secondary anti-rabbit IgG conjugated to ferromagnetic microbeads was used. Separation columns allowed the retention of magnetically labeled cells within the matrix. The magnetic fractions were eluted after removal of the column from the magnetic field. All fractions were analyzed for cellular morphology and by flow cytometry. The final enrichment of c-kit-positive cells in the magnetic fraction using fully active testes was in the range of 25-55% with a viability rate of 80-90%. The magnetic fractions of all three species were characterized by high numbers of diploid cells. Cytological analysis revealed a strong enrichment of spermatogonia. No haploid cells were retained in the magnetic fraction. In comparison to conventional procedures, magnetic cell separation is an efficient and fast approach for isolation of spermatogonia.

Magnetic Cell Sorting Is a Fast and Effective Method of Enriching Viable Spermatogonia from Djungarian Hamster, Mouse, and Marmoset Monkey Testes

In the highly organized and complex process of mammalian spermatogenesis, the development of an undifferentiated diploid germ cell into a fully differentiated and mature spermatozoon is orchestrated in a time frame unique for each species including man. If the various hormonal signals including environmental cues that play a critical part in initiating these events are not properly executed, various deficiencies including delay in sexual maturity or puberty are likely. In this study we have followed testicular development and spermatogenesis in the FSH receptor knockout (FORKO) mice from Day 7 onward by using histology and quantitative DNA flow cytometry. The drastic reduction in testicular weight and shrinkage of seminiferous tubules that occurred at this early age persisted into the adult stage in the FORKOs, suggesting inhibition of the initial developmental processes. The round spermatids that were clearly abundant on Day 21 in the wild-type and heterozygous males were few and present only in some tubules of the FORKOs. There were no elongated spermatids in FORKO males on Day 35. The sperm produced by Day 49 FORKOs were already aberrant, a feature that persisted into adulthood in these animals. As all these changes occurred in a background of normal circulating testosterone levels, we may conclude that the delay in testicular development is a consequence of the loss of FSH-receptor signaling. The delay in sexual maturity of FORKOs was accompanied by reduction in fertility as evidenced by mating studies. Based on these data we suggest that the FORKO mouse might be a useful experimental model to define the molecular mechanisms that underlie the delay in puberty.

https://bioone.org/journals/biology-of-reproduction/volume-65/issue-2/biolreprod65.2.522/Delay-in-Sexual-Maturity-of-the-Follicle-Stimulating-Hormone-Receptor/10.1095/biolreprod65.2.522.pdf

Hanumanthappa Krishnamurthy

Papers

Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice.

Qualitative and Quantitative Decline in Spermatogenesis of the Follicle-Stimulating Hormone Receptor Knockout (FORKO) Mouse

Activation of Extracellular-regulated Kinase Pathways in Ovarian Granulosa Cells by the Novel Growth Factor Type 1 Follicle-stimulating Hormone Receptor: ROLE IN HORMONE SIGNALING AND CELL PROLIFERATION

Magnetic Cell Sorting Is a Fast and Effective Method of Enriching Viable Spermatogonia from Djungarian Hamster, Mouse, and Marmoset Monkey Testes

Delay in Sexual Maturity of the Follicle-Stimulating Hormone Receptor Knockout Male Mouse