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ENDOCRINOLOGY

Why Do Alcohol and Sugar Make us Thirsty?

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Why does drinking alcohol or consuming sugar make us thirsty? An international study of mice in Texas and humans in Europe reveals an unexpected anti-dehydration mechanism.

In a study published today in Cell Metabolism, UT Southwestern researchers identify a hormone that acts on the brain to increase the desire to drink water in response to specific nutrient stresses that can cause dehydration. The findings are reported by Dr. David Mangelsdorf and Dr. Steven Kliewer — who have run a joint laboratory at UT Southwestern since 2002.

The Mangelsdorf/Kliewer laboratory has long studied the liver hormone FGF21, or fibroblast growth factor 21. In earlier research, they found that FGF21 acts via the brain’s reward pathway in mice to suppress the desire for sugar and alcohol in favor of drinking water.

“We knew that exposure to alcohol or sugar turns on production of FGF21 in the liver. What we now show is that this hormone then travels in the blood to a specific part of the brain, the hypothalamus, to stimulate thirst, thereby preventing dehydration,” said Dr. Kliewer, Professor of Molecular Biology and Pharmacology and holder of the Diana K. and Richard C. Strauss Distinguished Chair in Developmental Biology. “Unexpectedly, FGF21 works through a new pathway that is independent of the classical renin-angiotensin-aldosterone thirst pathway in the kidneys.”

In mice, the study revealed, the hormone regulated hydration (water drinking) in response to nutrient stress. In one experiment, the researchers found that normal mice and mice genetically unable to produce FGF21 drank similar amounts of water when given the typical chow diet. However, a high-fat/low-carbohydrate ketogenic diet stimulated water drinking in normal mice while mice genetically unable to produce FGF21 failed to increase water intake in response to that nutritional stress. Those findings confirmed the hormone’s role in the signaling pathway, the researchers said.

A second important finding in this study is the very strong response to the hormone in humans, Dr. Kliewer said.

In that part of the research, 21 study participants at the Medical University of Graz in Austria were randomly assigned to drink either a mixture of alcohol and juice, or juice alone. Hourly over four hours, researchers measured their FGF21 blood levels. In response to alcohol, FGF21 levels peaked at around two hours and fell after that.

“This suggests that FGF21 might someday be used as a drug to limit alcohol consumption and protect against its effects in people,” said Dr. Mangelsdorf, Chair of Pharmacology, Professor of Pharmacology and Biochemistry, and a Howard Hughes Medical Institute (HHMI) Investigator. “Those findings also suggest that FGF21 is regulated the same way in humans as in mice and that the process involves the expression and activation of certain proteins in the brain.”

The FGF21-induced thirst response appears to depend on another signaling pathway in the hypothalmus, the ?-adrenergic circuit, the researchers said.

“There are old studies from the 1970s suggesting that this pathway might regulate thirst. Our data suggest that FGF21 might work through that pathway as well,” said Dr. Mangelsdorf, who holds the Alfred G. Gilman Distinguished Chair in Pharmacology and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D.

For a long time, feeding behavior has been emphasized in metabolic research rather than hydration. This study suggests a change may be on the table, the researchers said.

“To put this in context, we always look at food intake, and the metabolic field has spent comparatively little time studying water intake. This study suggests that we should think more about hydration and how it might contribute to metabolism,” Dr. Kliewer said.

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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ENDOCRINOLOGY

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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