News, Notes, & Insights

Androgens Have Sex-Specific Effects on Adipose Tissue

It’s hard to figure out a hormone’s workings when it has opposite actions in men and women—such as androgens’ sex-specific metabolic effects. In men, androgen deficiency is linked to insulin resistance and obesity, and treatment with testosterone improves insulin sensitivity and reduces fat content. In women, the androgen excess of polycystic ovary syndrome cor- relates with insulin resistance and obesity.

Rodents do not seem to share this dichotomy, so researchers led by Charles T. Roberts Jr., Ph.D., of the Oregon National Primate Research Center in Beaverton, employed a nonhuman pri- mate model to determine if androgens’ sex-specific effects occur in fat tissue itself. They tested the effects of gonadectomy and hormone replacement on white adipose tissue in Japanese macaque males and rhesus macaque females.

In the males, in vivo androgen deprivation did not result in overt obesity or insulin resistance, pos- sibly due to the relatively short period of androgen deficiency, but it did induce the appearance of very small, multilocular white adipocytes. Testosterone replacement restored normal cell size and im- proved insulin sensitiv- ity in the adipose tissue.

The researchers used a novel ex vivo meth- odology to study the sex-specific properties and regulation of white adipose tissue under controlled culture conditions. Although ex vivo dihydrotes- tosterone treatment did not improve the insulin sensitivity of male white adipose tis- sue, in vivo testosterone replacement in androgen- deficient males had the effects described above, suggesting that androgens regulate male adipose insulin sensitivity. Female adipose tissue treated with androgens displayed elevat- ed basal fatty acid uptake but reduced insulin-de- pendent fatty acid uptake. Androgen-stimulated basal uptake was greater in the adipose tissue of ovariecto- mized females than in that of intact females.

In an upcoming Endocrinology* paper, the researchers say their results demonstrate that androgens are essential for normal adipogenesis in males and can impair es- sential adipocyte functions in females, strengthening the evidence that andro- gens have sex-specific ef- fects at the level of white adipose tissue.

Cancer Risk Increases with Insulin Levels in Type 2 Diabetes

Insulin therapy is crucial in treating type 2 diabetes mellitus, but high insulin levels have their own danger. Gathering data from Taiwan’s National Health Insurance Database and the National Cancer Research Registry, researchers at the National Taiwan University found high rates of cancer incidence as- sociated with use of insulin and oral insulin secretagogues.

Risk of various cancers such as liver, stomach, and pancreas were elevated when insulin supplement was the primary treatment. Breast and prostate cancer, however, showed no increased risk. Cancer risk is lower with the use of sul- fonylureas and glinides, designed to increase insulin expression, but remains high enough that carcino- genesis is a significant result of high serum insulin levels.

The study, to be published in The Journal of Clinical Endocrinology & Metabolism,* finds cancer risk de- creasing with use of insulin sensitiz- ers like metformin and thiazolidin- ediones (TZDs). Showing up mostly in colorectal cancer, cancer incidence is 8% lower with metformin and 10% lower for TZDs. To explain this, the researchers posit that insulin- sensitizing drugs have anti-cancer properties inhibiting growth and inducing cell death.

In the delicate balance of manag- ing diabetes, hyperinsulinemia can tip the scales toward even greater health risks. A greater emphasis on metformin and similar anti-diabetic medications might restore that balance, reducing the risk of cancer associated with insulin therapy.

Thyroid Cancer Type Tied to Genomic Instability

Evidence is building that a body’s instability at its most basic level—the genome—could tip it toward some cancers by accentuating the genetic abnormalities that underlie them.

One potential source of this instability is defects in telomeres, the specialized nucleoprotein structures that protect chromosome ends from damage by erosion, end-to-end fusion, and other threats. Several studies have reported evidence that abnor- mally short telomeres play an impor- tant role in the early development of cancer and chromosome instability.

A team of researchers led by Furio Pacini, M.D., at the University of Siena, Italy, now report genomic insta- bility’s role in familial papillary thyroid cancer (PTC). The researchers used conventional and molecular cytogenet- ic approaches to verify whether famil- ial PTC patients show a predisposition toward three indicators of genomic instability—telomere associations, telomere fusions, and spontaneous chromosome fragility. They analyzed these cytogenetic features in phytohe- magglutinin-stimulated T lymphocytes from familial PTC patients, unaffected family members, sporadic PTC patients, and healthy subjects.

The familial PTC patients had sig- nificantly more spontaneous telomeric associations and telomeric fusions than healthy subjects and sporadic PTC patients. The familial PTC patients also had a spontaneous chromosome fragility frequency slightly higher than that of healthy subjects and sporadic PTC patients, with many acentric frag- ments carrying telomeric sequences resulting from sub-telomeric chro- mosomal breakage. Tests of telomere length by quantitative fluorescence in situ hybridization found a statistical difference between healthy subjects and the other groups, with healthy subjects having longer sequences.

The researchers conclude in an article slated for publication in The Journal of Clinical Endocrinology & Metabolism* that telomere instabil- ity could be a factor underlying the predisposition of patients to develop this familial form of cancer.

Low Doses of BPA Affect Neural System

The U.S. Food and Drug Administration recently denied a request from an environmental group to ban the ubiquitous chemi- cal bisphenol A (BPA) from food and beverage con- tainers—but evidence of BPA’s endocrine-disrupting effects continues to mount. The latest comes from a study whose results suggest that BPA exerts a powerful impact on neural systems, including the estrogen- mediated brain functions of memory and learning.

Researchers led by Victoria Luine, Ph.D., of City University of New York, used ovariectomized rats to study the effects on recognition memory of BPA alone and of BPA in combination with doses of estrogens (17b-estradiol and 17a-estradiol) known to have effects.

They found that acute exposure to BPA altered estradiol-induced enhance- ments of spatial and non- spatial memory in adult female rats. BPA blocked enhancement of memory consolidation by both 17b- estradiol and 17a-estra- diol in a task-specific and dose-specific manner. In contrast, in the absence of estradiol, BPA did not af- fect memory performance.

The researchers also investigated dendritic spines as a mechanism for the memory effects, because chronic changes in estradiol alter both recognition memory and spine density in the medial prefrontal cortex and hip- pocampus. The effects were complex, and depended on the dose, timing, and duration of treatment. In the prefrontal cortex, BPA did not alter estradiol- dependent increases. In the hippocampus, BPA’s effect was additive with that of estradiol at times of memory consolidation (after 30 minutes), but blocked estradiol-caused increases in basal spines at times of memory retention (after 4 hours).

In an article accepted for publication in Endocri- nology,* the authors say their results raise important additional concerns about the chemical because these effects on estrogen-mediat- ed cognitive function were caused by BPA at levels be- low the safe daily limit set by the U.S. Environmental Protection Agency.

Gasping for Hypothalamic- Pituitary-Adrenal Function

A hot topic in current research is transgenera- tional effects of prenatal interventions. Administra- tion of synthetic glucocor- ticoids such as betametha- sone to mothers at risk for preterm delivery to hasten fetal lung maturation is a prime example. Although this treatment is highly effective in decreasing re- spiratory distress syndrome in the newborn, there may be long-term consequences, especially following ex- posure to multiple treat- ments. In animal models, these have been shown to include disruptions in renal, cardiovascular, and neurologic system function and, particularly, dysregula- tion of the hypothalamic- pituitary-adrenal (HPA) axis. This dysregulation not only persists in the long term, but also contributes to earlier development of metabolic conditions and hypertension. But what of the effects down the generational line?

Led by Stephen G. Mat- thews, Ph.D., at the Uni- versity of Toronto, Canada, scientists previously demon- strated that HPA down- regulation due to changes in gene expression happens in the hippocampus, hypo- thalamus, and the pituitary gland in male guinea pig first-generation offspring and in female offspring dur- ing the luteal phase of the reproductive cycle. Their current study investigates whether these effects carry through to the next generation and whether they are still sex specific. In their upcoming paper in Endocrinology,* the researchers report that the second-generation offspring of grandmaternal guinea pigs given betamethasone prenatally show significant differences compared to controls born to offspring of guinea pig mothers given saline. Males showed increased negative feedback in response to dexamethasone challenge (i.e., cortisol sup- pression), and young males exhibited less activity—a tendency to avoid open ar- eas, possibly due to anxiety. In females, pituitary func- tion was impaired, and they showed decreased negative feedback to dexamethasone challenge (i.e., no suppres- sion).

The researchers conclude that HPA function is af- fected in successive genera- tions of guinea pig mothers treated with synthetic glucocorticoids and that given the link between HPA function and anxiety, stress behavior is likewise signif- icantly altered. Perhaps it’s time to reexamine that cost/benefit ratio.

Androgen Receptor Mutation Linked with Hereditary Polyglutamine Disorder

Although the etiology of neurodegeneration was thought to involve abnormal protein aggrega- tion, that hypothesis has recently been scrutinized. In diseases involving androgen receptor (AR) dysregulation, such as spinobulbar muscular atrophy (SMBA), also known as Kennedy disease, mo- tor neuron loss does not seem to correlate with nuclear inclusion protein accumulation. Prior studies have shown that polyglutamine tract elongation disrupts AR tran- scription insofar as a membrane- associated AR induces nongenomic signaling in certain pathways with androgen stimulation. A new study puts these two findings together to explore a novel mechanism of SMBA pathogenesis.

Using NSC34, a cell line resem- bling motor neurons but lacking endogenous AR, scientists led by Norbert Bakalara, Ph.D., at the École Nationale Supérieure Chimie Montpellier, in France, induced expression of two AR mutants—one with a polyglutamine expansion (AR51Q) and loss of transcriptional activity and the other lacking the polyglutamine chain (AR0Q)—to examine effects on the c-jun signal- ing pathway. AR20Q was used as the control. An important mediator of apoptosis, c-jun is also implicated in neuronal foot process outgrowth. In their paper, to be published soon in Molecular Endocrinology,* the researchers report that AR51Q impairs cell viability by failing to activate the c-jun signaling pathway necessary to mount the appropriate response to cell stress and by dimin- ishing astrocyte outgrowth.

The researchers conclude that down-regulation of nongenomic AR signaling may contribute to SBMA onset. Because classic AR behaves differently—even paradoxically— than does membrane-bound AR in the presence of steroid hormone, po- tential new therapeutic approaches should consider both, they add.

Exercise After Liposuction Prevents Fat Regain

Liposuction is touted as a third weapon in weight loss after diet and exercise, but it can be a double- edged sword. Regrowth of fat and increased risk for cardiovascular disease have been observed. In a recent 6-month trial at the University of São Paulo, Brazil, 36 “normal-weight” women had a small amount of abdominal fat removed through liposuction. Then, 18 of them underwent a 4-month exercise program and the other 18 had no exercise training. Only the latter group regained fat, but not where the research- ers thought.

Instead of fat regrowth at the surgery site, the regain occurred in the visceral cavity between the internal organs. The study, to be published in The Journal of Clinical Endo- crinology & Metabolism*, suggests that a compensa- tory regain of fat might come from a decrease in the total energy expen- diture. By interrupting the system used in energy regulation, liposuction might force the body to go on alert and save what en- ergy it can. Because none of the patients increased their food intake, sudden fat loss is a likely cause of fat regain.

Why the regain oc- curred in the visceral cav- ity needs further study, but exercise clearly prevents it. The 4-month training program actu- ally protected the body against any compensatory regain of fat. The sudden increase of energy used during exercise or a longer-term rise in resting metabolic rate perhaps counteracted the body’s post-surgery response.

This is particularly important in abdomi- nal liposuction. Risk of cardiovascular disease and type 2 diabetes associates strongly with visceral fat. Encouraging its growth can increase the risk regardless of body mass index. Exercise closely following surgery can mitigate it.

Epigenetic Changes Play Role in Diabetes Development

The mechanisms underlying dia- betes are complex and multifactorial, and researchers who are breaking down their many components to make sense of them have identified another transcription factor that hyperglycemia can play havoc with.

Pancreatic duodenal homeobox 1 (PDX-1) is a homeodomain-contain- ing transcription factor that plays a key role in pancreatic develop- ment and function. Mutations in PDX-1 can cause a monogenic form of diabetes in humans; silencing of the Pdx-1 gene in the pancreatic b-cells of mice causes diabetes. In the mature pancreas, it is mainly expressed in islet beta cells, where it plays an important role in glucose-dependent regulation of insulin gene expression.

Charlotte Ling, Ph.D., of Lund University Diabetes Center in Malmö, Sweden, led a team that compared DNA methylation and mRNA expres- sion of PDX-1 in pancreatic islets of 55 nondiabetic donors and 9 type 2 diabetes mellitus (T2DM) patients.

PDX-1 expression was lower in the pancreatic islets of diabetes patients than in those from nondiabetic donors and correlated positively with insulin expression and glucose-stim- ulated insulin secretion in the islets. DNA methylation of PDX-1 correlated negatively with its expression in the islets. Methylation of the PDX-1 promoter and enhancer regions sup- pressed reporter gene expression in clonal b-cells.

Hyperglycemia decreased gene expression and increased PDX-1
methylation. In mouse clonal beta-cells exposed to high glucose, Pdx-1 expression decreased and Pdx-1 methylation increased.

The researchers say that their findings demonstrate that epigenetic modifications of PDX-1 can reduce its expression in human islets, which may lead to impaired insulin expression and secretion, and that hyperglycemia may be a factor be- hind increased DNA methylation and decreased expression of PDX-1. They conclude, in a paper coming out soon in Molecular Endocrinology,* that epigenetic modifications may play a role in T2DM development.

Pituitary Gland Regeneration Grows on Researchers

The mutability of pituitary gland cells in the context of fluctuating en- docrine needs led scientists to propose that stem cells participate in such ad- aptations. Recently, they pinpointed the location of these cells and found that they express Sox2, a transcrip- tional factor common to many stem cells. Scientists have also demonstrat- ed both that stem cells contribute to the restoration of some adult organs after tissue injury and that dividing (i.e., immature) cells such as the growth hormone (GH)-producing pituitary somatotrophs are capable of regeneration at early-postnatal age. Taken together, these findings beg the question—can pituitary gland cells also regenerate in the adult?

Led by Hugo Vankelecom, Ph.D., at the University of Leuven, Belgium, scientists established a transgenic mouse model of pituitary tissue damage. After injecting adult GH/ Cre-inducible diphtheria toxin recep- tor (iDTR) mice and control mice (not expressing the iDTR) with diphtheria toxin for 3 consecutive days, they used immunofluorescence to examine pituitaries 1 day and 1 week later to confirm somatotroph ablation. In their paper, to be published soon in Endocrinology,* the research- ers report that pituitary stem cells respond keenly to adult injury to contribute to somatotroph restora- tion, as evidenced by expansion of the stem cell locus and proliferation of stem cells. Remarkably, the stem cells reveal both Sox2, as expected, but also GH, which was not found in control pituitary stem cells.

The researchers concluded that stem cells repair adult pituitary tissue that has sustained injury. The next step is determining whether the stem cells morph into GH-pro- ducing cells or if surviving somato- trophs instead “de-differentiate” to a stem-cell state in the regenerative process. This future research will require more sophisticated GH-cell lineage tracking but will potentially unlock pathways that can be exploit- ed clinically, they add.

Testosterone Builds Bone and Raises Cholesterol in Transsexual Men

The making of a man is in his blood. Testoster- one dictates the advance of puberty in boys, gener- ally developing larger bone and muscle mass than es- trogen does in girls. Under cross-sex hormonal therapy in adulthood, the bodies of female-to-male transsexual persons (transsexual men) change in much the same way. Researchers at the University of Ghent, Bel- gium, measured increased bone and muscle mass in 50 transsexual men continuing testos- terone substitution sex-reassignment surgery (SRS) and compared them with 50 age- matched women. Their upcoming paper in The Journal of Clinical Endocrinology & Me- tabolism,* suggests that greater bone formation and resorption in transsexual men might actually be in response to the increase of muscle. They had no risk of low bone mass despite the lack of estrogen. Their periosteum, a membrane enveloping bone just under the skin, was larger com- pared to the female control group, perhaps due in part to low estrogen levels that inhibit periosteal growth.

An additional group of 16 transsexual men not yet undergoing testosterone substitution or SRS showed none of these changes. Their bodies were simi- lar to a control group of 16 age-matched women. Physical exercise made little difference in either trans- sexual group except in the periosteal circumference of those receiving testos- terone.

Testosterone substitu- tion was also associated with less fat mass in the larger group of transsexual men. Their fat distribution was more central, collecting more at the waist and in the visceral cavity. Total choles- terol, however, increased. Although transsexual men might not experience risk of bone loss during cross- hormonal therapy, their risk of metabolic complications may rise under the influ- ence of testosterone.

Maternal Diabetes Fits with Offspring Autism

Autism incidence has steadily risen over the past several decades, inciting a riot of investigation into its etiology in direct pro- portion to the abundance of theories about its cause and the number of ques- tions as yet unanswered. With epigenetics recently showing promise among these hypotheses, one more piece of the autism puzzle may have clicked into place.

Previous studies have demonstrated links be- tween maternal metabolic conditions, such as diabetes and impaired neurodevelop- ment, probably due to the fetal biologic response to high maternal glucose lev- els. Fetal hyperinsulinemia leads to greater oxygen use, which in turn causes hy- poxia and, ultimately, iron deficiency. Both conditions are known to harm human hippocampal develop- ment. Moreover, maternal cytokines produced in response to some metabolic conditions can cross the placenta, wreaking havoc in several neurogenera- tive processes and possibly causing development of seizure disorders.

Led by Paula Krakowiak, M.S., at the University of California, Davis, Scientists analyzed data from 1,004 children ages 2–5 years who participated in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study. The purpose was to determine relationships between maternal metabolic conditions—primarily type 2 diabetes and gestational diabetes but also hyper- tension and obesity—and fetal neurodevelopmental impairments. Among these children, 517 had been previously diagnosed with autism spectrum disorders (ASDs), 172 with devel- opmental delays, and 315 with typical development (control group). In their pa- per, to be published soon in Pediatrics,* the researchers report that children with an ASD (28.6%) or a develop- mental delay (34.9%) were more likely than children in the control group (19.4%) to have a mother with a metabolic condition. Addi- tionally, the ASD children of mothers with diabetes were also more likely to exhibit poorer expressive language skills. Hypertension did not seem to play a role here.

The researchers con- clude that metabolic condi- tions, particularly diabetes, and obesity are associated with developmental deficits ranging from language impairments to communi- cation and socialization dysfunction. With the prevalence of diabetes and obesity rising among reproductive-aged women, the significance of this finding is staggering.

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