News from the latest research

EFFECT OF CARBONATION ON BRAIN PROCESSING of Sweet Stimuli in Humans

Carbonation has been shown to change the mind’s perception of sweetness, eventually making it difficult for the brain to tell the difference between sugar and artificial sweeteners, according to an article recently published in the journal Gastroenterology.

The paper’s lead author, Rosario Cuomo, MD, of the University of Naples, says that this “study proves that the right combination of carbonation and artificial sweeteners can leave the sweet taste of diet drinks indistinguishable from normal drinks.”

Of course, carbonated beverages have been linked to myriad health problems, from obesity and diabetes to cardiovascular disease, and have been particularly related to an increased calorie intake. The authors wrote that taste “is the main sensory modality influencing food preferences and dietary behavior and affecting body weight, risk of chronic disease, and health.” They used functional magnetic resonance imaging to view the effects of carbonation on the brain when it processes sweet stimuli.

What they found was that the carbonation in soft drinks “tricks” the brain into thinking the body is receiving sweets and, therefore, rewarding the pleasure center. The mechanism could promote the consumption of carbonated drinks with low calorie content.

The study concludes, “CO2 modulates the perception of sweetness, reducing the global neural processing of sweetness, the processing of sucrose more than of As-Ac, and the processing difference between sweetening agents. This piece of information is of utmost importance for designing carbonated beverages and is relevant to the regulation of caloric intake.”

GLUCOCORTICOIDS Shown to Affect Adiposity

A paper recently published in the journal Molecular Endocrinology has demonstrated the essential role of glucocorticoid receptor (GR)–mediated negative feedback regulation in the paraventricular nucleus (PVN) of the hypothalamus, which cannot be compensated for by intact GR function in the pituitary or extra-hypothalamic areas.

While chronic exposure to elevated glucocorticoids is often associated with anxiety and despair-related behavioral changes, elevation resulting from disrupted PVN GR does not. This may refl ect adaptive mechanisms in other brain regions that attenuate GR activation, or that the normal circadian rhythm that is maintained in these animals allows compensation to occur, or that loss of GR in the PVN is protective for the high circulating glucocorticoid levels.

The researchers, led by Louis J. Muglia, MD, PhD, at Cincinnati Children’s Hospital Medical Center, showed the substantial differences in phenotypes that can emerge with conditional deletion of different floxed versions of the same gene. This can be due to deletion efficiency or structural/ functional characteristics of the recombined locus.

The authors concluded that excess glucocorticoids affect adiposity to different degrees in males and females, suggesting an important interaction of glucocorticoids and sex steroids on metabolism/adipocyte physiology.

NEW DRUG TARGET Could Prevent Diabetes and Obesity

New research from Cleveland Clinic’s Lerner Research Institute showed that blocking the function of a protein called ABHD6 in animal models protects against all diseases driven by eating a high-fat diet, including obesity, diabetes, and liver disease. Th is protein is thought to regulate the brain’s endocannabinoid system, which is involved in a variety of processes, including metabolism, craving, and hunger.

These studies suggested a new biological pathway for preventing high-fatdiet-induced obesity, according to Cleveland Clinic research published today in the journal Cell Reports.

Th e researchers wrote that they used combined in vivo lipidomic identification and in vitro enzymology approaches to show that ABHD6 can hydrolyze several lipid substrates, “positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction.”

“Obesity and diabetes are major threats to global public health and economic vitality, and an urgent need exists for new treatments to off set the health problems associated with these conditions,” lead author J. Mark Brown, PhD, said in a Clinic news release.

“We have identified ABHD6 as a new potential drug target for the battle against obesity and related disorders,” Brown continued. “The search for a ‘magic pill’ to prevent excessive weight gain has long been sought after. These new findings suggest that drugs inhibiting ABHD6 may simultaneously activate fat burning, increase physical activity, and block the formation of new fat in the liver.”

New Therapeutic Potential for ENDOMETRIAL CANCER

A study recently published in the journal Endocrinology detailed a novel approach to treating endometrial cancer.

The authors wrote that in many human cancers, the tumor suppressor, p27kip1 (p27), a cyclindependent kinase inhibitor critical to cell cycle arrest, undergoes perpetual ubiquitin-mediated proteasomal degradation by the E3 ligase complex SCFSkp2/Cks1 and/or cytoplasmic mislocalization; lack of nuclear p27 causes aberrant cell cycle progression and cytoplasmic p27 mediates cell migration/metastasis.

Endometrial cancer is the most common cancer of the reproductive organs for women in the U.S., with almost 50,000 new cases diagnosed every year. Risk factors include age, total number of menstrual cycles, skin color (white women develop this cancer more often, but black women are more likely to die from it), obesity, and diabetes.

The scientists, led by Leslie I. Gold, PhD, at New York University, injected two-month-old female ovariectomized mice with mitogenic estrogen (E2), a hormone that they had previously shown induces degradation of p27 by the E3 ligase SCFSkp2/Cks1 in primary endometrial epithelial cells (EECs) and endometrial carcinoma (ECA) cell lines, suggesting a pathogenic mechanism for type I ECA, an E2-induced cancer. Treatment of endometrial carcinoma cells-1 (ECC-1) cells with small molecule inhibitors of Skp2/Cks1 E3 ligase activity (Skp2E3LIs; Timothy Cardozo) stabilizes p27 in the nucleus, decreases p27 in the cytoplasm, and prevents E2-induced proliferation and degradation of p27 in ECC-1 cells and primary ECA cells.

The estrogen-primed mice injected with Skp2E3LIs (Bo Rueda) showed significant increases in nuclear p27 and reduced proliferation of EECs by 42% – 62%. Skp2E3LIs are specific inhibitors of proteolytic degradation that pharmacologically target the binding interaction between the E3 ligase, SCF-Skp2/ Cks1, and p27 to stabilize nuclear p27 and prevent cell cycle progression. These targeted inhibitors have the potential to be an important therapeutic advance over general proteasome inhibitors for cancers characterized by SCF-Skp2/ Cks1-mediated destruction of nuclear p27.

The researchers concluded, “These inhibitors might, therefore, be effective in E2-induced endometrial carcinoma in which p27 is both, degraded in the nucleus and/or sequestered in the cytoplasm. Furthermore, their effects should be applicable to other human cancers having similar pathology of low levels of p27 and high levels of Skp2/Cks1 in the nucleus and/or, high cytoplasmic p27.”

LOW TESTOSTERONE May Lead to Heart Problems

Men with low testosterone may have to worry about more than loss of body hair and muscle bulk, decreased sex drive, and depression. A review of literature recently published in the Journal of Clinical Endocrinology and Metabolism showed that low levels of the important male sex hormone may be linked to cardiovascular problems as well.

These findings come at a time when more and more men are being prescribed testosterone replacement therapy, even though some experts disagree on the therapy’s efficacy. Th e reviewers, led by Johannes Ruige, MD, PhD, of Ghent University Hospital in Belgium, says that in their research, they were able to make a “modest connection” between testosterone and cardiovascular disease, based on a “growing body of evidence.”

Th e researchers reviewed studies on testosterone and cardiovascular disease published between 1970 and 2013, and found studies on low T and increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, endothelial dysfunction, and impaired left ventricular function.

“A specific pathogenesis did not come forward,” Ruige said in an Endocrine Society press release, “but perhaps less frequently investigated events may play a role, such as thrombosis where a blood clot develops in the circulatory system or arrhythmia, where there is a problem with the heart beat or rate. Based on current findings, though, we cannot rule out that low testosterone and heart disease both result from poor overall health.”

However, the authors noted, testosterone therapy has not been proven to either specifically benefit or harm cardiovascular health. “The cardiovascular riskbenefit profile of T therapy remains largely evasive in view of a lack of welldesigned and adequately powered randomized clinical trials,” they wrote.

The reviewers concluded that even though treatment with T to restore T concentrations to this optimal window have not been proven to be beneficial with respect to cardiovascular disease, males with low T and specific cardiovascular conditions such as heart failure or coronary artery disease may benefit from substitution therapy. However, a cautious, restrained approach to T therapy in aging men is advisable, pending clarification of benefits.

BARIATRIC SURGERY Shows Promise in “Curing” T2D in Obese Patients

Patients with type 2 diabetes mellitus (T2DM) who underwent bariatric surgery showed positive outcomes in controlling T2DM, with a significant amount achieving long-term remission, according to a study recently published in the journal Annals of Surgery.

Scientists, led by Stacy Brethauer, MD, at the Cleveland Clinic, evaluated clinical outcomes of 217 patients with T2DM who had bariatric surgery between 2004 — 2007 and then had at least a five-year follow up. Of those participants, 162 had Roux-en-Y gastric bypass surgery, 32 had gastric banding, and 23 had sleeve gastrectomy. The researchers observed that 24% of total patients achieved long-term remission of T2DM, while 26% achieved partial remission — no longer “diabetic,” but they retained blood glucose levels higher than normal. A little more than a third of all participants showed some improvement in A1C from baseline, while 16% showed no change.

Brethauer said in a clinic news release that 80% of the diabetic patients still control their blood glucose levels (A1c < 7%) five years after surgery, while nearly 30% of the gastric bypass patients had normal blood glucose levels for five years after surgery without taking medications. “This study confirms that the procedure can off r durable remission of diabetes in some patients and should be considered as an earlier treatment option for patients with uncontrolled diabetes,” he added. The study defined complete remission as, “A1C less than 6% and fasting blood glucose (FBG) less than 100 mg/dL off diabetic medications.” They noted that a shorter duration of T2DM before surgery and keeping the weight off after bariatric surgery “predicted long-term remission.” Conversely, patients who had T2DM for a longer duration and had gained weight again after the surgery experienced a recurrence of T2DM after initial remission (about 19% of participants). The authors concluded, “Bariatric surgery can induce a significant and sustainable remission and improvement of T2DM and other metabolic risk factors in severely obese patients. Surgical intervention within five years of diagnosis is associated with a high rate of long-term remission.”

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