A look at the latest research

UNLIGANDED THYROID HORMONE RECEPTOR
May Play Role in Development

A novel animal study has uncovered clues to embryo developmental timing and growth rates. Th e study, recently published in Endocrinology, should prompt further research and improve the understanding on the role of the thyroid hormone (T3) signaling pathway during early development, according to lead author Yun-Bo Shi, PhD, of the Eunice Kennedy Shriver National Institute Child Health and Human Development.

T3 affects adult metabolism and postembryonic development in vertebrates by binding to thyroid hormone receptors (TRs) to regulate gene expression. Of the two TR genes, TRα and TRß, TRα is more ubiquitously expressed. The authors wrote, “During development, TRα expression appears earlier than T3 synthesis and secretion into the plasma. This and the ability of TRs to regulate gene expression both in the presence and absence of T3 have implicated a role of unliganded TR during vertebrate development.” Th e researchers also noted that it is difficult to study the role of unliganded TR during development in mammals due to the difficulty to manipulate the uterusenclosed, late-stage embryos.

Since it was recently shown that transcriptional activator like eff ector nucleases (TALENS) can be used to knockout/knockdown genes in amphibians and zebrafish, the investigators used the amphibian Xenopus tropicalis (tadpole) to study how unliganded TR aff ects its development. That animal’s embryogenesis produces a free feeding tadpole in the absence of T3. “Subsequently,” the authors wrote, “as endogenous T3 becomes available, the tadpole is transformed into a frog in a metamorphic process that changes essential every organ/tissue of the animal.”

The scientists designed TALENS to mutate the TRα gene in the tadpoles and found that knockdown of TRα enhances tadpole growth in premetamorphic tadpoles, likely through increased growth hormone gene expression. “More importantly,” the authors wrote, “the knockdown also accelerates animal development, with the knockdown animals initiating metamorphosis at a younger age and with a smaller body size. On the other hand, such tadpoles are resistant to exogenous T3 treatment and have delayed natural metamorphosis.”

Shi and his team concluded that their studies have not only directly demonstrated a critical role of endogenous TRα in mediating the metamorphic eff ect of T3 but also revealed novel functions of unliganded TRα during postembryonic development — regulating both tadpole growth rate and the timing of metamorphosis. The authors wrote that “mammalian development likely also utilizes unliganded TR, especially during early embryogenesis when T3 levels are low, to coordinate organ development and maturation, similar to premetamorphic tadpole development.”

“Given the conservation in vertebrate development,” Shi says, “our findings suggest that it is very likely that unliganded TR will affect mammalian embryo growth and development during the early stages when there is little or no circulating T3.”

Time-Restricted Feeding May Prevent Metabolic Diseases

Confining access to food to a set time may prevent metabolic diseases, a recent animal study published in the journal Cell has shown.

Researchers led by Satchidananda Panda, PhD, of the Salk Institute for Biological Studies, say that novel interventions are needed to treat obesity, since current therapeutics are limited and off er only modest improvements. “Lifestyle interventions,” they wrote, “including changes in diet, reduced caloric intake, and increased exercise, have been the fi rst-line therapy in eff orts to combat obesity and metabolic diseases. However, these lifestyle changes require constant attention to nutrient quality and quantity and physical activity.” Panda and his team note that success with lifestyle interventions has been limited to a small number of individuals.

The investigators, therefore, set out to study the effects of timerestricted feeding (TRF) “against different nutritional challenges including high-fat, high-fructose, and high-fat-plus-high-fructose diets, all of which have been shown to cause dysmetabolism.” They subjected 392 12-week-old wild-type mice to different feeding regimens to evaluate TRF’s effectiveness against different diet types, eating patterns, and existing obesity. Diets were high in fructose or fat or both, but the mice were either fed within a nine-hour window or allowed to eat ad libitum feeding (ALF). The calories consumed for all mice were equal, but the TRF mice gained less weight over a 12-week period.

The researchers then wanted to test longer durations of TRF and its eff ectiveness on preventing weight gain, so they allowed mice access to food for nine, 12, or 15 hours. Food consumption was again equivalent, but longer daily feeding times “resulted in larger increases in body weight” (26% gain for nine-hour TRF versus 43% gain for 15-hour TRF). Mice fed ad libitum (FA) gained 65% under these conditions.

TRF was even shown to be effective against the occasional slip-up. The mice alternated between fi ve days of TRF (weekdays) and two days of (ALF) (weekends) for 12 weeks (5T2A). “Th e legacy eff ect of TRF over this time scale was remarkable,” the authors wrote, “with only 29% body weight gain for 5T2A mice compared to 61% weight gain for FA mice.” TRF also promoted weight loss and weight stabilization in the obese mice once they were switched to TRF. The subset of FA mice that were switched to TRF showed modest weight loss and maintained that weight until the end of the study.

Finally, TRF had far-reaching effects on glucose and protein metabolism. “ALF mice showed constitutively higher activation of the gluconeogenesis pathway, a characteristic of insulin resistance,” the authors wrote. “All mice on TRF were protected against insulin resistance. Irrespective of adiposity, when TRF mice were challenged with a glucose bolus they were able to restore normoglycemia much faster than ALF mice.”

Panda and his team concluded that TRF shows great potential in counteracting human obesity and the metabolic disorders that go with it.

Exercise Regimens Offer Little Benefit for One in Five People with T2D

As many as one in five people with type 2 diabetes (T2D) do not see any improvement in blood sugar management when they engage in a supervised exercise regimen, according to a new scientific review published in the Journal of Clinical Endocrinology & Metabolism.

“Since obesity and lack of physical activity are two key risk factors for type 2 diabetes, physicians frequently recommend exercise and other lifestyle interventions to prevent or manage the disease,” says one of the study’s authors, Lauren Marie Sparks, PhD, of Florida Hospital and the Sanford-Burnham Medical Research Institute in Orlando, Fla. “Most people benefit from an exercise regimen, but our research indicates that a significant minority of individuals with type 2 diabetes do not experience the same improvements in metabolism due to their genes.”

The researchers examined clinical studies in which people with T2D participated in exercise regimens, as well as animal and genetic studies on the topic. They found that around 15% – 20% of individuals with T2D did not see any improvement in their blood sugar control, insulin sensitivity, or muscle mitochondrial density. Genetic and animal studies indicate this resistance to exercise is encoded in DNA and can be handed down through generations.

“More research is needed to determine which people with or at risk of developing T2D will respond to an exercise program and which will not,” Sparks says. “Genetic and epigenetic patterns could hold the key to differentiating between the two groups. With that information in hand, we can target specific interventions and treatments to the individuals who will benefit most and identify novel treatment approaches to help those who do not respond to exercise.”

PROSTATE CANCER PATIENTS Not Getting Needed Bisphosphonates

A research letter recently published in the Journal of the American Medical Association claimed that too few prostate cancer patients are being prescribed bisphosphonates, even though those drugs are needed to temper the increased risk of bone loss and fracture due to androgen-deprivation therapy (ADT).

The study, led by Shabbir Alibhai, MD, MSc, of the University Health Network in Toronto, analyzed a Canadian database of 35,487 men ages 66 and older who were diagnosed with prostate cancer between January 1, 1995 and December 31, 2012 who had undergone orchiectomy or received at least six months of ADT. They then looked through drug database claims for any bisphosphonate claim within 12 months of ADT initiation and separated the cohort into three groups: all nonusers of bisphosphonates, those with prior osteoporosis, and those with prior fragility fracture.

The investigators found that bisphosphonate claims among all nonusers increased from 0.35 per 100 persons in 1996 –1997 to 3.4 per 100 persons in 2010 – 2012. “Even among those with prior osteoporosis or fragility fracture, rates remained low,” the authors wrote. Among all three groups, peak bisphosphonate claims occurred in 2007 – 2009, with a high of 11.89 per 100 persons in those with prior osteoporosis.

The researchers concluded that bisphosphonate prescription rates among men receiving ADT remained low throughout the study period, suggesting “limited awareness among clinicians regarding optimal bone health management.”

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