News, Notes, & Insights

Researchers Find Androgen Clues in Bird’s Mating Dance

When a small Panamanian bird called a golden-collared manakin (Manacus vitellinus) goes courting, he performs an amazing acrobatic dance of rapid jumps and forceful wing snaps that pop like a firecracker to get a female’s attention. A team of researchers led by Barney A. Schlinger, Ph.D., of the University of California, Los Angeles, wanted to find out if androgens fueled the bird’s musculature for his rigorous athletic display.

Earlier work showed that manakins injected with radiolabeled testosterone accumulate radioactivity in the spinal cord, indicating the heightened presence of androgen receptors in this area, which is heavily used during copulation and courtship rituals. To follow up on this finding, the scientists compared the spinal cords of manakins and zebra finches for levels of androgen receptor, estrogen receptor a, and aromatase. The androgen receptor level was much higher throughout the manakin spinal cords, but levels of estrogen receptor and aromatase were not.

The researchers then injected fluorescent tracers into androgen receptor–sensitive wing muscles of manakins to map the distribution of their motor neurons. This showed abundant androgen-receptor mRNA in the cervical and lumbosacral spinal enlargements and the dorsal root ganglia attached to these enlargements.

In an article awaiting publication in Endocrinology,* the researchers posit that androgens have widespread actions on motor and sensory circuits in the manakin spinal cord, including circuits that control three sexually dimorphic wing muscles. Their previous studies have found elevated androgen receptor expression in manakin skeletal muscles, suggesting that a unique androgen-sensitive neuromuscular phenotype facilitates these athletic courtship displays.

“There are few animal models to understand the complex coordinated neuromuscular systems simultaneously employed by most athletes,” Schlinger told Endocrine News. Discovering that steroid hormones act not only on skeletal muscles but also on the spinal cord, sensory and motor neurons, and link back to the brain, lays the groundwork for understanding the homones’ effects on humans.

Vitamin D, a Defense Against Diabetes?

A new study presents more evidence that a person’s vitamin D level may indicate whether or not he or she is at risk for type 2 diabetes mellitus (T2DM). Recent research shows that compared to people with high vitamin D levels, people with low vitamin D levels are more than 50 percent more likely to have high blood pressure, high triglycerides, high blood glucose, low HDL cholesterol, and a big waistline—all prime risk factors for this disease.

Using data from the Diabetes Prevention Program study, Joanna Mitri, M.D., M.S., of Tufts Medical Center, who presented the research at ENDO 2012,* reports that participants with the highest risk of metabolic syndrome had a vitamin D blood concentration of approximately 12 ng/ mL. The risks to those with a vitamin D concentration of 30 ng/mL were reduced by 48 percent. A vitamin D level of 20–30 ng/mL is considered healthy by the Institute of Medicine.

The association between Vitamin D and T2DM risk has been documented
in the past, but this study includes people of diverse racial and ethnic backgrounds, Mitri said. “These include minority groups that are already at higher risk of diabetes.”

If a causal relationship can be established with future studies, vitamin D’s availability would be an easy and inexpensive therapy for defense against the disease.

Progesterone Receptor Binding Could Be Key to Treating Endometrial Disease

Dysfunctional progesterone signaling can contribute to the pathology of several gynecological diseases, but the role of progesterone has received much less attention than that of estrogen. Researchers from Baylor College of Medicine in Houston decided to correct this imbalance by examining the molecular mechanisms underlying progesterone signaling via the progesterone receptor.

Led by Francesco J. DeMayo, Ph.D., the team defined the genome-wide binding sites of progesterone receptor—its cistrome—in the murine uterus using chromatin immunoprecipitation, followed by massively parallel sequencing (ChIP-seq). This process first identified 6,327 progesterone receptor–binding sites in ovariectomized mice. However, after exposure to progesterone, the number of binding sites identified increased nearly three-fold.

Sequence analysis showed that 73 percent of these binding sites contain a progesterone response element or a half-site motif recognized by the progesterone receptor. The method identified progesterone receptor–binding sites in many progesterone-target genes known to regulate uterine function, which confirmed the validity of the researchers’ approach.

The researchers identified an unexpected regulatory role for uterine progesterone in circadian rhythm gene expression, leading them to speculate that progesterone regulation of the circadian clock could be involved in the window of receptivity for embryo implantation.

The ChIP-seq data revealed an abundance of Sox (sex-determining region on the Y chromosome–related high mobility group box) motifs. In particular, the data revealed Sox17 as a direct transcriptional progesteronereceptor target gene in the uterus, indicating that Sox17 is a potential mediator of action.

In their upcoming Molecular Endocrinology* article, the researchers say their upcoming analysis provides the first insights into these molecular mechanisms and will provide an important data set for future investigation of progesterone signaling through its receptor. The data will be useful in the identification of novel cooperating transactivating factors in normal uterine regulation, and could lead to the development of therapies to combat endometrial disease.

BAT Linked to Bigger Bones

Once thought to exist only in infants, brown adipose tissue (BAT) is now known to be present in adults. Researchers have also found that it does more than regulate thermogenesis, its main role in infants, and conclude that brown fat influences musculoskeletal development in children and adolescents.

Positron emission tomography (PET) and computed tomography (CT) scans reveal that pediatric patients with more BAT also had more muscle than patients with less. During puberty, BAT and muscle increase at comparable rates and share structural and functional traits, suggesting a relationship. Animal studies show that the tissue may regulate mesenchymal stem cell differentiation into osteoblasts rather than adipocytes, thus building up bone and reducing fat. Finally, muscle is a primary source of anabolic mechanical stimuli for bone tissue. All of these clues suggest that BAT is involved in musculoskeletal integrity.

Scientists, led by Vicente Gilsanz, M.D., at Children’s Hospital Los Angeles, California, explored the possible association between the amount of BAT and the development of leg bones and whether muscle contributes to this relationship, by reviewing PET and CT scans images of tissue in 40 children and teenagers who had been successfully treated for various cancers. In their paper, to be published soon in The Journal of Clinical Endocrinology & Metabolism,* the researchers report that the greater the volume of BAT the larger the femoral crosssectional area and cortical bone area, even after accounting for height, weight, and gender. Factoring in muscle mass diminished BAT’s role somewhat, which leaves the overall relationship unclear. Figuring out the dynamics of this interplay of bone, muscle, and BAT could lead to the development of therapies to mitigate bone loss.

Vitamin D Receptor Signals Healthy Cardiovascular System

If vitamin D protects the cardiovascular system, what role does the vitamin D receptor (VDR) play?

Despite the strong correlation between cardiovascular disease and vitamin D deficiency, little is known about the underlying mechanism beyond the possibility that vitamin D regulates T lymphocytes and obstructs foam cell formation by macrophages. These, in turn, are important players in promoting atherosclerosis. Directly uncovering how the VDR fits in is a logical next step.

Scientists led by Yan Chun Li, Ph.D., at the University of Chicago, deleted the VDR from low-density lipoprotein receptor (LDLR)–null mice, and assessed the impact on atherosclerotic lesion formation at the innominate artery, ascending and descending aortas, and the aortic root of the heart. In their upcoming paper in Molecular Endocrinology,* the researchers report that LDLR-null mice lacking VDR showed increased lesion formation at the innominate artery and the ascending aorta compared with controls, even after modifying the experiment to eliminate other potentially confounding factors such as differences in plasma cholesterol levels. Initially, the VDR-negative mice showed lower cholesterol levels, which is inconsistent with increased atherosclerosis. On deleting T and B lymphocytes through bone marrow transplantation, increased atherogenesis remained seen at the innominate artery and the ascending aorta in the experimental model, pointing to leukocytes/macrophages as the VDR signaling sites of action for the antiatherosclerotic activity.

The researchers conclude that macrophage vitamin D–receptor signaling inhibits foam cell formation and, ultimately, atherogenesis in mice. In VDR-negative mice, significant up-regulation of the macrophage renin–angiotensin system (RAS), crucial for atherogenesis, suggests that the macrophage VDR signaling abrogates RAS locally. Thus, more potential for therapeutic and prophylactic use of vitamin D is put forward.

Prostate Not Damaged by Hormonal Contraception

Male hormonal contraception (MHC) is on the advance. A number of studies show high rates of success in suppressing pituitary gonadotropin secretion through combined androgenprogestin therapy. However, the prostate normally uses androgen to stay in good health and the long-term effects of the extra androgens from MHC, such as the potential for an increase in prostate cancer risk, are poorly understood. In a three-month trial, researchers, primarily at the University of Washington and the Fred Hutchinson Cancer Research Center, found no increase in prostate androgen levels in 32 healthy men age 25–55 years.

Use of transdermal testosterone therapy (trans T) increased dihydrotestosterone (DHT) in the blood but not in the prostate. Trans T plus the progestin depomedroxyprogesterone acetate (DMPA) decreased prostate DHT by 40 percent. DMPA may account for this drop by inhibiting the conversion of testosterone to DHT in the prostate. Combining trans T with dutasteride, a 5a-reductase inhibitor, achieved decreases in both serum and prostate DHT for the same reason. In neither case was androgen-regulated gene expression reduced, possibly due to high testosterone levels in the prostate compensating for low DHT.

Despite changes in testosterone and DHT concentrations, the prostate proved able to maintain its own androgen levels. These results, to be published in The Journal of Clinical Endocrinology & Metabolism,* are direct evidence that androgen therapy does not necessarily increase prostate androgens, and thus may not make prostate disease more likely. Instead, inhibiting DHT in the prostate might lower the risk of cancer. These results support a green light for MHC development.

Thymulin Gene Therapy May Alleviate Reproductive Problems

Researchers have found a potential gene therapy approach to the reproductive problems associated with thymus dysfunction.

During the perinatal period, a functioning thymus is necessary for proper maturation of the pituitarygonadal axis. Congenitally athymic female mice show severe ovarian dysgenesis and a host of neuroendocrine derangements.

Because considerable evidence suggests that the peptide thymulin is important in thymus-pituitary communication, researchers led by Rodolfo G. Goya, Ph.D., of the University of La Plata in Argentina, examined the preventive action of neonatal thymulin gene therapy (NTGT) at the hypothalamic, pituitary, ovarian, and uterine levels in congenitally athymic female mice. Thymulin consists of a biologically inactive peptide called FTS coupled in an equimolecular ratio to the zinc ion, which activates it. The researchers injected the mice with an adenoviral vector containing a synthetic DNA sequence that encoded a biologically active analog of thymulin called metFTS.

This gene therapy approach restored the serum thymulin levels in the athymic mice. Morphometric analysis showed that the athymic mice had fewer brain gonadotropinreleasing hormone neurons and pituitary gonadotropic cells than heterozygous controls, but the NTGT brought these cells to normal levels and prevented the premature ovarian failure typically observed in athymic mice. Serum estrogen levels were low in the athymic mice but were partially raised by the NTGT. The NTGT also prevented the delay in the age of vaginal opening that occurs in athymic mice.

In a previous study, the researchers showed that NTGT therapy prevented the deficits in luteinizing hormone and follicle-stimulating hormone normally seen in these mice. They conclude in an upcoming Endocrinology* article that their new results complement these previous findings and together support the hypothesis that thymulin is a key player in the thymus-reproductive axis. The researchers recommend thymulin gene therapy to treat reproductive pathologies associated with thymus dysfunction.

Poor Sleep Worsens Resting Energy Use

A bad night’s sleep can mean more than just morning crabbiness. Obesity is common with sleep deprivation and usually attributed to bad eating habits as compensation for the lack of rest. Researchers at the National Institute of Diabetes and Digestive and Kidney Diseases’ Sleep Extension Study Group instead found a relationship between poor sleep quality and changes in a person’s resting energy expenditure (REE).

In their cross-sectional study of 126 obese individuals, to be published soon in The Journal of Clinical Endocrinology & Metabolism,* high degrees of sleep apnea directly associate with increased REE. Stress hormones might trigger the release of adrenaline and other catecholamines in a sympathetic response, raising heart rate and blood pressure. Hypoxia, a known result of sleep apnea, decreases REE, but any effect on the initial increase has not yet been seen.

Sleep apnea also associates strongly with a high respiratory quotient (RQ), indicating that carbohydrates are being oxidized instead of fat. Carbohydrate oxidation provides quicker energy but less of it, requiring more carbohydrate intake. Fat accumulates instead of being used, strongly predicted by a high RQ.

These changes appear more in men. Of the 126 participants, 30 were men and had higher morning levels of serum cortisol and catecholamines. They also slept 30 minutes less than their female counterparts and typically had a 70 percent increase in calorie intake per day as their sleep apnea worsened. With poor sleep quality a growing concern, the impact on weight control and stress response is enough to keep a person up at night.

BPA Linked to Transgenerational Behavioral Changes

The once nearly ubiquitous commercial plasticizer bisphenol A (BPA) has received a lot of negative press in the past several years. Studies have implicated BPA in conditions from obesity to neurological impairment.

A new study adds an insidious twist to the damage BPA inflicts. Led by Emilie F. Rissman, Ph.D., at the University of Virginia, Charlottesville, scientists explored for the first time whether BPA’s effects on behavior are transgenerational. They fed one group of mouse dams a chow supplemented with BPA in an amount correlating with what would typically be found in humans. A control group was fed a phytoestrogen-free chow. After mating the dams and establishing pregnancy, some embryos were removed for whole brain examination to determine gene expression.

In their paper, to be published soon in Endocrinology,* the researchers report that BPA firstgeneration offspring exhibited less social investigation, such as side-byside interactions, but had a greater tendency to display playful behaviors such as sniffing, digging, and jumping. They also noted that activity in BPA male and female mice was similar rather than dimorphic as in control mice. In secondthrough fourthgeneration offspring, the two changes persisted but in reverse. They now exhibited more social investigation than controls and less play-seeking, but again, without a sex-related difference. The brains revealed lower transcript levels of estrogen receptors, vasopressin, and oxytocin, all of which are known behavior mediators. Two of these gene changes, vasopressin and oxytocin, persisted in the fourth generation, and of note at that time, oxytocin was only reduced in males whose great-great grandmothers had been exposed to BPA.

The researchers conclude that BPA alters social behaviors transgenerationally, possibly via DNA methylation. Because disruption occurred at BPA doses comparable to reported human levels, BPA’s heritable effects may have implications for neurological disorders such as autism in humans.

Plasticizer Possibly a Cause of Obesity in Children

Bisphenol A may be getting all the press, but another common chemical used to soften plastic may be just as dangerous. Diethylhexyl phthalate (DEHP) is one in a long line of phthalates that might increase the risk of childhood obesity by as much as five times the norm. Many plastic and non-plastic products, from vinyl flooring to soap, use phthalates to retain flexibility. Because plasticizers are used in flooring and wall coverings, food containers, cosmetic products, and some medical devices (such as blood storage bags, intravenous medical tubing), phthalates are found in almost all categories of personal care products for infants, children, and adults, resulting in widespread non-occupational human exposure through multiple routes. Newborn babies are particularly vulnerable to phthalate exposure through medical devices, explained Mi-Jung Park, M.D., a pediatric endocrinologist at Inje University College of Medicine and Sanggye Paik Hospital in Seoul, who presented the findings at ENDO 2012.*

In recent research, DEHP levels were measured in 105 obese children compared to 99 non-obese children, all age 6–13 years. On average, the obese children showed DEHP blood levels of 107 ng/mL, compared to 53.8 ng/mL in their non-obese counterparts.

Park correlates high DEHP levels with the high percentages of fat mass and body mass index consistent with obesity. The increased risk of obesity according to the elevation of serum DEHP levels was independent of possible factors, such as physical activity and daily calorie intake.

Though DEHP does not conclusively cause childhood obesity, it is a suspected hormone-altering agent.

A Picture Worth a Thousand Calories

As advertising knows, seeing is wanting. A new study demonstrates that images of high-calorie food significantly increase the desire for food.

Using functional magnetic resonance imaging sessions, researchers studied the brains of 13 obese Hispanic women age 20–25 years as they viewed images of high-calorie foods such as ice cream and cupcakes, and low-calorie foods such as fruits and vegetables. The participants also viewed non-food items. During scanning, each participant rated hunger and desire for food on a scale of 1 to 10, with 10 representing the greatest hunger and desire. Brain regions controlling appetite and reward processing lit up (indicating increased activity) when participants viewed the high-calorie images and ratings increased for sweet and savory foods.

Halfway through one scan, participants drank 50 g of glucose,
equivalent to the amount of sugar in a can of soda, and 50 g of fructose halfway through the second scan. Both increased hunger and a desire for savory foods, but fructose had the greater effect on the brain’s reward regions.

Presenting the study at ENDO 2012,* Kathleen Page, M.D., of the University of Southern California, Los Angeles, chose the participants based on the high risk obese Hispanic women face for continued weight gain. Their reactions to dual stimulation by food images and sugar intake have immediate implications for appetite control. Food advertising is prevalent as are added sweeteners like high fructose corn syrup. In a society confronting overeating and obesity, they seem more than just a feast for the eyes.

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