News, Notes, & Insights

Obesity Linked to Taste Sensitivity

Humans have evolved a highly developed sense of taste that steers us away from toxic substances, signaled by bitterness, and toward sweet, sour, savory, salty, and other tastes that we perceive as pleasant. This evolutionary adaptation, however, varies in sensitivity among individuals, and has far-reaching implications for children, who establish lifelong eating patterns based on taste. Studies have shown that those with less taste sensitivity, possibly due to fewer taste buds, need to eat more to feel satiated.

Susanna Wiegand, M.D., at the Charité Children’s Hospital, Universitätsmedizin Berlin, in Germany, led a team to ﬁnd out whether obese children have reduced taste sensitivity. They gave a series of taste strips soaked with varying concentrations of one of the ﬁve main tastes to 99 obese and 94 normal-weight subjects ages 6–18 years and asked them to rate each strip from 1 for “no taste” to 5 for “very strong taste.” In their paper, recently published online in Archives of Disease in Childhood, the researchers report that obese children scored an average of 12.6 out of 20, whereas normal-weight children scored an average of 14.1 out of 20, indicating that the normal-weight children have keener taste perception. Moreover, girls more accurately identiﬁed tastes than boys, as did older children; however, the investigators found no signiﬁcant difference among ethnicities. Importantly, 85 percent of the obese participants had low socioeconomic status.

The researchers conclude that taste sensitivity varies with obesity status, and that endocrine and paracrine levels, which also correlate with obesity status, might inﬂuence the taste mechanism. They add that future larger studies should control for socioeconomic factors to conﬁrm the association between obesity and taste sensitivity in view of eventually developing related obesity-prevention strategies.

Low Vitamin D Levels May Cause MS Flare-Ups

Patients with multiple sclerosis (MS) experience more active disease when their vitamin D levels drop, according to a study reported in Annals of Neurology. Ellen M. Mowry, M.D., M.C.R., now assistant professor of neurology at the Johns Hopkins University School of Medicine, reported the findings. Mowry is principal investigator of a multicenter clinical trial of vitamin D supplementation in patients with MS.

In exploring a possible link between vitamin D deﬁciency and MS severity, the researchers, based at the University of California, San Francisco, compared vitamin D levels in study participants’ blood to magnetic resonance imaging (MRI) results. Their goal was to see if the overall number or the number of active lesions, indicating lesscontrolled disease, correlated with changes in vitamin D levels.

Myelin is a fatty protein that insulates nerves and transmits electrical signals between them. It’s instrumental to movement, vision, and speech. With MS, the body’s immune system attacks myelin in the brain and spinal cord. Myelin degradation shows up as white spots or lesions on MRIs. In the most common form of MS, called relapsing-remitting MS, the myelin attacks come and go and with them, disease symptoms.

From 2004 to 2009, the researchers drew annual blood samples and performed MRIs with contrast dyes on 469 subjects with relapsingremitting MS. The researchers found each 10 ng/ml increase in vitamin D levels correlated with a 15 percent lower risk of new lesions and a 32 percent lower risk of active lesions.

Although the research is promising, Mowry cautions it’s preliminary and notes that researchers haven’t determined whether vitamin D supplements will reduce symptoms or prevent MS altogether. In the ongoing randomized trial, researchers will compare the effects of two vitamin D supplement dosages.

Protein Complex Critical to Fertility

The Scribble/Lgl/Dgl polarity protein complex is crucial to spermatogenesis and may be a potential target for treatment of male infertility, according to a new research study. In their paper soon to be published in Endocrinology [endojournals.org], researchers studied Sertoli and germ cells from 20-day-old rat testes to investigate the role Scribble/Lgl/Dgl plays during spermatogenesis—the process by which sperm become mature enough to fertilize an egg.

The researchers’ ﬁndings showed that this protein complex is crucial to spermatogenesis because its disruption perturbs spermatid polarity and cell adhesion in the testis, according to lead researcher C. Yan Cheng, Ph.D., from the Center for Biomedical Research at Population Council in New York City.

Infertility affects about 15 percent of married couples, and the male factor is responsible in about 50 percent of those couples, Cheng said. “These ﬁndings suggest that an alteration of the Scribble/ Lgl/Dgl protein complex’s function, such as might be induced by environmental toxicants, could be the ‘cause’ of some cases of unexplained male infertility,” Cheng added. His study’s ﬁndings may be of beneﬁt to physicians who specialize in treating reproductive problems.

Leptin Homolog Found in Fruit Flies

The humble fruit fly has made key contributions to our understanding of genetics, and now it’s poised to affect our knowledge of metabolism. Researchers believe they have found in Drosophila a functional homolog of the human hormone leptin, which plays a key role in controlling appetite.

Akhila Rajan, Ph.D., and Norbert Perrimon, Ph.D., of Harvard Medical School in Boston, looked at Drosophila fat bodies, the analogs of vertebrate adipose tissue that convey nutrient status to the ﬂy brain. The fat bodies produce a cytokine called unpaired 2 (upd2) in response to dietary fat and sugars. The upd2 in turn leads to the secretion of Drosophila insulin-like peptides, which promote systemic growth and fat storage.

Flies that the researchers genetically engineered to lack upd2 function had reduced growth and altered energy metabolism, much as humans who lacked leptin would. The researchers reversed these effects by inserting the human leptin gene into the ﬂies. The human leptin substituted functionally for the upd2, even acting as a ligand in the signaling pathway that regulates insulin secretion. This genetic dopplegänger also led to the secretion of the key Drosophila insulin-like peptides.

Differences in human and ﬂy biology had appeared to limit the usefulness of ﬂies in metabolic studies. For example, in humans, pancreatic β-cells secrete the key hormones involved in metabolism. In contrast, the fruit ﬂy cells with insulin-producing function are found in the brain, but the researchers found similarities. Because cytokines play central roles in mammalian nutrition sensing and metabolic homeostasis, the scientists looked for a similar process in ﬂies. Their study illustrates a cytokine-mediated pathway regulating insulin secretion according to nutrient availability.

In an article recently published in Cell, Rajan and Perrimon say their ﬁnding that the key human hormone leptin is so closely related to Drosophila upd2 indicates that the Drosophila model can be used to investigate leptin biology.

Hydrogen Sulﬁde’s Role in Diabetes

Hydrogen sulfide not only contributes to that awful odor of rotten eggs, it might also contribute to the pathogenesis of diabetes.

Along with nitric oxide and carbon monoxide, hydrogen sulﬁde has been classiﬁed in the newly identiﬁed group called gasotransmitters. These gaseous signaling molecules have multifaceted physiological functions, and hydrogen sulﬁde appears to negatively affect metabolism. Researchers at Lakehead University in Thunder Bay, Ontario, Canada, led by Rui Wang, M.D., Ph.D., recently found that it inhibits pancreatic insulin secretion from islets and β-cell lines.

Given the key metabolic roles of the pancreas and liver, the researchers followed up these ﬁndings by investigating the role of hydrogen sulﬁde in glucose metabolism and insulin signaling in the HepG2 human hepatoma cell line and in mouse hepatocytes.

They found that hydrogen sulﬁde down-regulated glucose uptake and glycogen storage, while at the same time enhancing the activity of an enzyme that increased glucose production. This combination of decreasing glucose input and enhancing glucose output contributes to hyperglycemia, which is a major symptom of insulin resistance.

In an article awaiting publication in Endocrinology [endo. endojournals.org], the researchers say that the interaction of hydrogen sulﬁde and insulin in the liver plays a pivotal role in regulating insulin sensitivity and glucose metabolism. Hydrogen sulﬁde contributes to the development of hepatic insulin resistance, a key aspect of the metabolic perturbations leading to diabetes.

Hearing Impairment in Diabetes: A Meta-Analysis

Diabetes patients, listen up: your disease may affect your hearing, according to an upcoming article in The Journal of Clinical Endocrinology & Metabolism [jcem.endojournals.org]. Led by Chika Horikawa, R.D., M.S., at the Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine in Japan, investigators conducted a metaanalysis of the prevalence of adult-onset hearing impairment in patients with and without diabetes.

The researchers searched the MEDLINE (1950 to May 30, 2011) and EMBASE (1974 to May 30, 2011) databases. The group selected studies in which data on both hearing-impaired and non-hearing impaired subjects was presented, in which hearing impairment was assessed by puretone audiometry that included at least 2 kHz of frequency range, and in which hearing impairment was categorized as chronic, progressive, sensorineural, or without speciﬁed cause. Thirteen eligible studies were identiﬁed, for a total of 20,194 participants and 7,377 cases.

People with diabetes were twice as likely to be hard of hearing as non-diabetic individuals. The prevalence was even more pronounced in diabetes patients under 60 years of age: compared to nondiabetic patients, they had 2.5 times the risk of hearing impairment, while those over age 60 had 1.5 times the risk.

The authors hypothesized that diabetes may negatively affect the microenvironment of the ear, leading to the progression of hearing impairment, and that the role of glycemic control in preventing hearing loss in diabetic patients should be studied.

Pubertal Changes in Hormones May Contribute to Mood Disorders

As sex hormones rise during puberty and transform young bodies and minds, girls suffer from stress-related mood disorders at a higher rate than their male counterparts. The effects of sex hormones on the hypothalamic-pituitary-adrenal (HPA) axis may contribute to important differences in the sexes.

One stress-response hormone, corticotropinreleasing factor (CRF), may be a key player, because its receptors are concentrated in sensitive areas of the forebrain such as the amygdala, which regulates arousal, mood, and the HPA axis. Evidence indicates that one of these receptors, CRF1, initiates neuroendocrine and behavioral responses to stress, but CRF2 decreases these responses. For example, CRF1 agonists increase anxiety-like behavior in rats, and CRF2 agonists decrease this behavior. CRF1 knockout mice are less anxious, and CRF2 knockout mice are more anxious.

To see how the binding properties of these receptors change with age and sex, Jill M. Weathington, M.S., and Bradley M. Cooke, Ph.D., of the Neuroscience Institute at Georgia State University in Atlanta, measured them in the amygdala of prepubertal and adult rats.

Before puberty, the binding densities of the receptors were indistinguishable between the sexes in four subregions of the amygdala. After puberty, a clear difference emerged between the sexes in every subregion. CRF1 binding was greater in adult females than in males, but CRF2 binding was greater in adult males than in females. In a paper accepted for publication in Endocrinology [endo.endojournals.org], the researchers say their study demonstrates that CRF receptors undergo maturational changes consistent with a divergence of the stress response system in males and females during puberty. This sex difference could play a role in predisposing women to stress-related mood disorders.

Gastric Bypass and Ovulation

Infertility is one complication of obesity that has perplexed researchers. For example, does it affect ovulation and sexual function? Gastric bypass surgery offers a novel perspective on this poorly understood relationship.

Richard S. Legro, M.D., at the Pennsylvania State University College of Medicine, Hershey, Pennsylvania, led a team to ﬁnd out whether Roux-en-Y gastric bypass, the most frequently performed gastric bypass in the United States, would improve the frequency and quality of ovulation and sexual function in 29 formerly morbidly obese women ages 18–40 years.

In their paper, to be published soon in The Journal of Clinical Endocrinology & Metabolism [jcem. endojournals.com], the researchers report that post-surgical weight loss resulted in shorter menstrual cycles though of normal duration, speciﬁcally the follicular phase shortened while the luteal phase remained constant, and increased sexual desire and arousal. Other measurements, such as bone mineral density and level of facial sebum, an indication of clinical hyperandrogenism, did not change signiﬁcantly. Notably, and despite the researchers’ hypothesis to the contrary, ovulatory function and frequency did not improve signiﬁcantly.

The researchers conclude that morbid obesity and body composition do not signiﬁcantly affect ovulation.

Low IGF-I Linked to Alzheimer’s in Men

It is widely accepted that the endocrine hormone, insulin-like growth factor (IGF-I), contributes to the body’s aging process. New research suggests it might also play a role in Alzheimer’s disease in elderly men.

In a study, appearing in The Journal of Clinical Endocrinology & Metabolism [jcem.endojournals.org], a team of French researchers led by Emmanuelle Duron, M.D., Ph.D., Olivier Hanon, M.D., Ph.D., of Broca Hospital and Jacques Epelbaum, M.D., of Centre for Psychiatry and Neuroscience UMR 894 Inserm, Paris Descartes University in Paris, investigated whether a link exists between IGF-I and insulin-like growth factor binding protein (IGFBP-3) serum levels and cognitive impairment, including Alzheimer’s disease.

The study included 694 participants older than 65 years (218 men and 476 women), of whom 481 had memory complaints. Those participants were given cognitive tests and were diagnosed with either Alzheimer’s disease or mild cognitive impairment. The remaining 213, without memory loss complaints, comprised the control group. The researchers found a signiﬁcant link between low serum levels of IGF-I and IGFBP-3 and Alzheimer’s disease in men but not in women. For instance, in men, IGF-I was 137 ± 69 ng/ml in Alzheimer’s disease, but 172 ± 91 ng/ml in the controls. IGFBP-3 was 3,675 ± 1,542 ng/ml in the Alzheimer’s disease group, compared to 4,488 ± 1,893 ng/ml in the controls.

The investigators write that these results “justify a longitudinal study to evaluate whether circulating IGFI/IGFBP-3 are determinants of cognitive decline according to gender.”

Potassium Bicarbonate Counteracts Effects of High-Salt Diet

Potassium bicarbonate supplements can counteract some of the negative effects of high sodium chloride intake, a new study asserts.

The dangers of too much salt in the diet are well known, and one of them is the induction of a low-grade metabolic acidosis associated with bone resorption and protein loss. To test whether alkaline mineral salts can counter this effect, researchers led by Judith Buehlmeier, Ph.D., of the German Aerospace Center in Cologne, conducted a randomized, crossover study of eight healthy males. During a control period, the subjects were checked for the effects of eating a diet very high in sodium chloride. They then ate the same diet along with potassium bicarbonate supplements.

During the potassium bicarbonate period, the subjects’ urinary excretion of potentially bioactive free glucocorticoids and free cortisone dropped 14 percent. Their urinary excretion of calcium declined 12 percent, and excretion of the bone resorption marker, N-terminal telopeptide of type I collagen, dropped 8 percent. The researchers measured phenylalanine hydroxylation as a marker of net protein catabolism and found that the supplements led to a decrease just below the level of statistical signiﬁcance. The bonepreserving properties of the potassium bicarbonate did not compensate for the full metabolic consequences of the high-sodium diet, perhaps because acidosis is just one of several factors contributing to bone catabolism when sodium intake is high. Other processes, such as hormonal or osteoimmunological effects and ion-exchange could also be contributing in ways that the acid-base balance would not affect.

In an article to be published in The Journal of Clinical Endocrinology & Metabolism [jcem. endojournals.org], the researchers conclude that in the face of high dietary salt intake, potassium bicarbonate can induce a postprandrial shift to a more alkaline state that reduces metabolic stress. This shift leads to an anti-catabolic state featuring decreased bone resorption and protein wasting, which could have long-term beneﬁts for the musculoskeletal system.

Smoking Exacerbates Effects of Dietary Fat on Liver

Accumulating evidence suggests that smoking also contributes to fatty liver disease, adding liver pathology to the long list of cardiac, pulmonary, and metabolic disorders smoking is already known to affect. Moreover, a high rate of hepatic steatosis occurs in obese individuals. A new study examines whether fats and smoking are connected in developing fatty liver, which typically leads to more serious liver disease.

Led by Amiya P. Sinha-Hikim, Ph.D., at the Charles R. Drew University of Medicine and Science, Los Angeles, scientists fed mice a high-fat diet (HFD) comprised of 60 percent fat, causing common obesity complications, including visceral fat, hyperglycemia, insulin and leptin resistance, and fatty liver. Control mice ate normal chow. The team injected either nicotine or saline twice daily into mice from both groups. A separate pair of groups was additionally given the lipolysis inhibitor acipimox plus water or drinking water alone. In their paper, to be published soon in Endocrinology [endo.endojournals. org], the researchers report that HFD mice injected with nicotine showed increased oxidative stress, hepatic triglycerides, and hepatocellular apoptosis, with disruption of the adenosine monophosphate kinase signaling pathway, causing increased lipolysis and hepatic lipogenesis.

The researchers conclude that a high-fat diet and smoking synergistically lead to fatty liver disease. Their model can be used to develop an effective treatment at the molecular level, they add.

Prostate Cancer Treatment Could Target Estrogen Receptor β2

As prostate cancer advances, it can morph into forms that stymie effective therapies. Increased knowledge of the variants can provide fresh approaches to treatment. Androgen ablation, the frontline adjuvant treatment, loses effectiveness when the disease advances into an androgenindependent state. Once in that state, the disease often metastasizes to bone. In a search for ways to counteract this dangerous progression, researchers are looking at the role of estrogen receptors.

The estrogen receptor, ERβ, has several variants, and the main one, ERβ1, acts as a tumor suppressor with anti-metastatic properties in the prostate. However, the expression of ERβ1 drops during cancer progression, whereas expression of the variant ERβ2 grows. A team of researchers led by Anders Ström, Ph.D., of the University of Houston, Texas, studied the actions of these variants in the prostate cancer cell line PC3, which is often used as a model to study bone metastasis.

In their study of the effects of ERβ1, the most prominent ﬁndings were its simultaneous repression of cell proliferation and bone metastasis genes. It affected multiple cellcycle genes at both the mRNA and protein levels. It strongly down-regulated RUNX2, an important gene in bone formation and bone metastasis.

In contrast, ERβ2 upregulated RUNX2 at the mRNA level. ERβ2 also increased the expression of Twist1, a factor whose expression strongly correlates with high Gleason scores in prostate carcinoma. ERβ1 inhibited a large number of proliferation markers, and ERβ2 had opposite effects.

These results led the researchers to the conclusion that in PC3 cells, ERβ1 acts as a tumor suppressor, whereas ERβ2 increases proliferation and up-regulates factors involved in bone metastasis. Writing in Molecular Endocrinology [mend.endojournals.org], the authors say that ERβ2 deserves more study as a possible new target for prostate cancer treatment.