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ENDOCRINOLOGY

Why Is It Harder for Females to Gain Weight?

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For years, scientists have observed that when male and female mice eat the same high-fat diet, the males gain significantly more weight than the females. The reasons for this difference between sexes are not completely understood, but a new study published in the journal Nature Communications proposes that part of the answer may be in the brain.

“One of my research goals is to better understand the role the brain plays in body weight control,” said senior author Dr. Yong Xu, associate professor of pediatrics and of molecular and cellular biology and the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital. “In this study we propose a novel mechanism that may contribute to this difference between sexes.”

It’s been proposed that two main factors are likely to be involved in gender differences in body weight control; the sex chromosomes and the sex hormones. Males have one X and one Y chromosome, and females have two X chromosomes, but scientists understand very little about which genes on the sex chromosomes contribute to this issue. Males’ major sex hormone is testosterone, and females have high levels of estrogen and progesterone in their blood. Scientists agree that these hormones probably play a main role in regulating body weight.

“Differences in sex chromosomes and in sex hormones are important, but we have always wondered whether there is a third group of factors that may also contribute to the sex differences in the ability to regulate body weight,” Xu said. “We think ours is among the first studies looking at the brain to understand weight control differences between males and females.”

A closer look at the weight control center of the brain

Previous work had shown that the brain has several neuron populations that are very important for weight control. In this study, Xu and his colleagues determined whether these populations were different between male and female mice.

“One of the most important functions of all neurons is firing electrical signals. That’s how neurons talk to each other and to other tissues,” Xu said. “We compared the firing rate of many types of neurons between males and females and found a few that fired differently. We focused on one type, called POMC neurons, located in the hypothalamus.”

“POMC neurons in the hypothalamus help maintain normal body weight by inhibiting appetite and promoting energy expenditure in response to chronic high fat diet feeding,” said first author Dr. Chunmei Wang, an instructor in the Xu lab.

“We tested the firing rate of POMC neurons using electrophysiological techniques,” said first author Dr. Yanlin He, postdoctoral associate in the Xu lab. “Our results show that female POMC neurons fire faster than male neurons.”

But why do female POMC neurons fire faster than male’s? Xu and his colleagues screened POMC neurons for gene expression and found many genes that are expressed differently between males and females. One of the genes, TAp63, is expressed more in females than in males.

“We know from previous work that when we knock out the gene TAp63 in the entire body of a mouse, the animal becomes obese,” Xu said. “Here, we knocked out the gene only in POMC neurons and strikingly, this change did not affect male mice. On the other hand, female mice developed male-like obesity.”

Knocking out TAp63 not only affected weight control in females, it also decreased the firing activity of female POMC neurons to the level of male’s. Knocking out TAp63 in males, however, did not affect the firing rate of their POMC neurons.

These findings led the researchers to propose a novel mechanism that may contribute to sex differences in weight control. Female POMC neurons express higher levels of TAp63, which leads the neurons to fire faster than males. This results in the females having less appetite, spending more energy and therefore being more protected than males from gaining weight. The researchers think that these results may facilitate the future development of gender-specific therapeutic strategies for obesity and associated metabolic disorders.

“We think that our findings suggest that, in addition to studying chromosome and hormonal differences between males and females, scientists should also pay attention to this third category of factors,” Xu said. “We hope our study will encourage other researchers to continue investigating this line of research.”

ENDOCRINOLOGY

High Prevalence Of Restrictive Lung Disease In People With Type 2 Diabetes

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Breathlessness and conditions of restrictive lung disease (RLD), such as pulmonary fibrosis, may be a late complication of type 2 diabetes. These are the key findings of a joint study undertaken by researchers from the German Center for Diabetes Research (DZD) and the German Center for Lung Research (DZL) under the leadership of the University Hospital Heidelberg. The latest results have been published in the journal Respiration.

One in four patients in outpatient treatment settings suffer from breathlessness. Acute and chronic lung diseases are usually the main causes. Studies show that many people with interstitial lung disease (IDL) also suffer from type 2 diabetes. But do patients with type 2 diabetes also have a higher incidence of lung and respiratory diseases? Could breathlessness, IDL and RDL be a consequence of diabetes? These questions were investigated for the first time in a study by researchers from the German Centre for Diabetes Research (DZD) and the German Centre for Lung Research (DZL) at Heidelberg University Hospital.

The research team, headed by Dr. Stefan Kopf, comprised 110 patients with long-term type 2 diabetes, 29 patients with newly diagnosed type 2 diabetes, 68 patients with pre-diabetes and 48 non-diabetic patients (controls). The study participants were examined for metabolic control, diabetes-related complications, breathlessness, and lung function. It was found that people with type 2 diabetes are significantly more likely to suffer from breathlessness and RLD than the control group. RLD was found in 27% of patients with long-term type 2 diabetes, in 20% of patients with newly diagnosed diabetes, and in 9% of patients with pre-diabetes. Patients with pronounced symptoms and RLD also showed CT-morphologically a fibrosating interstitial lung disease. There were also differences in the morphological analysis of the lung tissue of subjects with and without diabetes. Patients with diabetes had increased pulmonary fibrosis.

In addition, the study showed that RLD is associated with albuminuria. In the disease, urinary albumin levels are elevated. This may be an indication that lung disease and kidney disease may be associated with diabetic kidney disease (nephropathy).

“Increased breathlessness, RLD, and interstitial lung anomalies can be associated with type 2 diabetes,” said first author Stefan Kopf, MD, of the Department of Endocrinology, Diabetology and Clinical Chemistry at University Hospital Heidelberg, summarizing the study results.

“In this study, the prevalence of RLD was 20 to 27 percent in patients with diabetes. Moreover, the radiological and histological analyses suggest an association with fibrosing interstitial lung anomalies,” added Professor Hans-Ulrich Kauczor, MD, Medical Director of Diagnostic and Interventional Radiology at University Hospital Heidelberg.

“The current study as well as findings from animal experiments show a significant connection between restrictive lung diseases and diabetes mellitus,” said Professor Michael Kreuter, MD, of the Thorax Clinic / University Hospital Heidelberg.

“We therefore suspect that lung disease is a late consequence of type 2 diabetes,” said last author Professor Peter P. Nawroth, MD, medical director of the Department of Endocrinology, Diabetology and Clinical Chemistry at University Hospital Heidelberg and member of the Scientific Advisory Board of the DZD. Patients with diabetes, nephropathy and breathlessness should therefore be examined regularly for RLD.

Background

Interstitial lung disease (ILD) is the term for a heterogeneous group of different lung diseases affecting the interstitial tissue of the lung (interstitium) and the alveoli. In restrictive lung disease (RLD) lung expansion is restricted. Restrictive lung disease is a category of conditions that includes pulmonary fibrosis.

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ENDOCRINOLOGY

What is More Important in Determining Body Fat- Exercise or Genetics?

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With obesity now a global epidemic, there is increased focus on risk factors that contribute to weight gain, especially in postmenopausal women. Although many women may blame genetics for their expanding waistlines, a new study shows that as women age they are more likely to overcome genetic predisposition to obesity through exercise. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Previous studies have suggested that the genetic influence on body mass index (BMI) increases from childhood to early adulthood. However, there has been little research on the effect of obesity genes later in life and whether they can be overcome through lifestyle modification, including exercise. In the article “Physical activity modifies genetic susceptibility to obesity in postmenopausal women,” results are published from the linear regression analysis of more than 8,200 women from the Women’s Health Initiative. Those results suggest that physical activity reduces the influence of genetic predisposition to obesity, and this effect is more significant in the oldest age group (women aged 70 years and older).

These findings additionally support guidelines for promoting and maintaining healthy behaviors, especially in older adults, to maximize quality and longevity of life.

“We are born with our genes, but this study suggests that we can improve our lives and health with exercise, regardless of genetics,” says Dr. JoAnn Pinkerton, NAMS executive director. “As women age, exercise has been shown to improve muscle mass, balance, and bone strength. It also invigorates brain cells, is associated with less arthritic pain, and improves mood, concentration, and cognition. Regardless of age, genes, and amount of abdominal fat or BMI, regular exercise can improve health.”

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New Findings Show Shivering And Exercise Promote The Same Fat-burning Mechanism

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Sad but true, we don’t all respond equally to exercise. Researchers at Joslin Diabetes Center have uncovered a new kind of clue to this variable response — a hormone whose levels in the bloodstream rise sharply in exercise as well as in cold.

The finding came from the first comprehensive study of fat-controlling hormones (known as lipokines) in exercise.

“This is a whole new area in research on exercise metabolism, and we seem to have found another mechanism by which exercise can have beneficial effects,” says Laurie Goodyear, Ph.D., Head of Joslin’s Section on Integrative Physiology and Metabolism and senior author on a report on the work published in Cell Metabolism.

Experiments in both humans and mice have shown that levels of one lipokine, with the unwieldy name of 12,13-diHOME, climb significantly in exercise, unlike the levels of other lipokines analyzed.

The study followed up on research published last year in joint work with the lab of Joslin’s Yu-Hua Tseng, Ph.D. This collaboration explored the release of lipokines from brown fat, which can burn energy in people or other mammals exposed to cold. In both humans and mice, the researchers demonstrated that the 12,13-diHome molecule was released from brown fat during cold exposure and offered beneficial metabolic effects.

“We found it very striking that when we then analyzed lipokines in exercise, the same lipokine that increased with cold also increased with exercise,” says Goodyear, an Associate Professor in Medicine at Harvard Medical School.

The Joslin researchers began by measuring levels of lipokines before exercise, immediately after exercise and three hours after exercise in the blood of 27 healthy male volunteers of various ages. When measured immediately after exercise,

“12,13-diHOME really stood out quite dramatically,” says Goodyear.

The scientists followed up by studying another set of volunteers, 12 healthy young people (split evenly between women and men) without regular exercise routines. Again, levels of the lipokine generally climbed substantially during exercise. Additionally, the scientists found that, in general, the more fit people were, the greater their resting levels of 12,13-diHOME.

The team next studied lipokines in exercising mice and saw similar results.

“When mice do a single bout of exercise, we see an increase in 12,13-diHOME,” Goodyear says.

“We also saw an increase after exercise training.”

Next, the investigators looked at molecular clues to the source of the lipokine and discovered that brown fat was a likely suspect. This was confirmed when the scientists removed most brown fat from mice and found that 12,13-diHOME levels in exercise dropped sharply.

“It seems to be the first example of a hormone released from brown fat that might regulate some of the metabolic effects of exercise,” Goodyear notes.

Researchers around the world look for ways to increase energy expenditure, and thus reduce obesity, by boosting brown fact activity. “Most of our data suggests that exercise doesn’t ramp up the energy expenditure of brown fat, but here, exercise is clearly having an effect on brown fat,” she says.

Further work in both mice and mice muscle cells that were given 12,13-diHOME revealed that the lipokine acts as a signal to boost the use of fatty acids as fuels, Goodyear adds.

She and her colleagues are broadening and deepening their research on the role of the lipokine, and other lipokines that decrease during exercise, in larger human cohorts as well as in further animal studies.

“The more knowledge we have about exercise and how it works, the better we can understand how to combat metabolic disease,” she says.

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