Postnatal Obesity Triggered During Pregnancy

During pregnancy, the health of the mother and the intrauterine environment can have dramatic and lasting effects on the child.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease that affects 0.5-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum.

In this issue of the Journal of Clinical Investigation, Catherine Williamson and colleagues at Imperial College London studied the long term impact of ICP in a cohort of Finnish families. They found that as teenagers, individuals born to women with ICP had altered metabolic profiles and increased BMI.

To further understand this effect, Williams and colleagues developed a mouse model of ICP and found that offspring of ICP mothers were more susceptible to metabolic disease and diet-induced obesity.

In the companion commentary, Susan Murphy of Duke University points out that the mouse model of ICP may also be useful in identifying other factors that predispose individuals to metabolic syndrome.

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Longest-Ever Intervention Study Investigating Whether Weight Loss Reduces The Risk Of Heart Disease For Patients With Type 2 Diabetes

A landmark study investigating the long-term effects of weight loss on the risks of cardiovascular disease among patients with Type 2 diabetes has now concluded, with significant results published in the New England Journal of Medicine.

Conducted at the University of Pittsburgh and at clinical facilities throughout the United States, the multicenter clinical trial investigated the effects of an intensive lifestyle intervention program, intended to achieve and maintain weight loss in overweight or obese people with Type 2 diabetes, on rates of cardiovascular disease. Begun in 2001, the trial enrolled more than 5,000 people at 16 clinical centers across the United States and is the longest intervention study of its type ever undertaken for patients with diabetes.

John Jakicic, chair and professor in the Department of Health and Physical Activity in Pitt's School of Education and Director of the Physical Activity and Weight Management Research Center, served as principal investigator for the University of Pittsburgh's role in the study. He, along with colleagues throughout the University, is among the researchers comprising the national Look AHEAD (Action for Health in Diabetes) Research Group, which carried out the study and authored the New England Journal of Medicine paper.

Among the study's main findings is that weight loss among members of the study's Intensive Lifestyle Intervention group, provided with a program of weight management and increased physical activity, resulted in no difference in heart attacks and strokes when compared with the study's control group, the Diabetes Support and Education group, which was provided with only general health information and social support.

The effect of the intervention program on weight loss, however, was significant: Participants in the intervention group lost 8.7 percent of their initial body weight after one year of the study versus 0.7 percent among the control group's members; the intervention group also maintained a greater weight loss, 6 percent of their initial weight, versus 3.5 percent for the control group, at the study's conclusion.

The Look AHEAD study is the first to achieve such sustained weight loss. A weight loss of 5 percent or more in short-term studies is considered to be clinically significant and has been shown to improve control of blood pressure, blood sugar, cholesterol, and other risk factors. Comparable weight loss can also help prevent the development of Type 2 diabetes in overweight and obese adults.

"While the findings from the Look AHEAD study did not support that engagement in a weight- loss intervention was effective for reducing the onset of cardiovascular disease incidence or mortality, this does not mean that overweight adults with diabetes should not lose weight and become more physically active," said Jakicic. "Rather, there is an overwhelming amount of evidence from this study to date that has shown that weight loss and physical activity were associated with numerous other health benefits.

"These include improving physical function and quality of life, reduction in risk factors such as lipids and blood pressure with less reliance on medication, better diabetes control with less reliance on medication, improved sleep, psychological and emotional health benefits, and many others," Jakicic said. "Thus, adults with diabetes can begin to realize many of these health benefits with even modest reductions in body weight and modest increases in physical activity."

The study sought to determine whether weight loss achieved with a lifestyle program would help individuals with diabetes live longer and develop less cardiovascular disease. While short-term studies had shown that weight loss improved control of blood sugar and mitigated risk factors for heart disease and stroke in overweight and obese individuals with Type 2 diabetes, the longer-term effects of weight loss were not well studied. In particular, it was unknown whether weight loss achieved with a lifestyle intervention alone could reduce the risk of heart disease in people with Type 2 diabetes.

Type 2 is the most common form of diabetes, affecting approximately 25 million Americans over the age of 20. Complications of Type 2 diabetes include heart disease and stroke, high blood pressure, blindness, kidney disease, the nervous system disease known as neuropathy, and amputations. The total cost of Type 2 diabetes in 2012 was estimated to be $245 billion. This disease, for which there is no cure but which involves ongoing treatment, can be managed with diet, physical activity including regular exercise equal to at least 30 minutes of brisk walking each day, modest weight loss, and a variety of medications. The Look AHEAD study has shown that these lifestyle factors are effective for improving the management of Type 2 diabetes.

Study participants were individuals between 45 and 75 years of age with Type 2 diabetes and a body-mass index of 25 or greater. Sixty percent of the study participants were women, while 37 percent were from ethnic and racial minority groups.

The University of Pittsburgh's General Clinical Research Center and Clinical Translational Research Center served as participating clinical sites, with researchers here recruiting more than 330 participants over a three-year span. Jakicic credited the Division of Endocrinology within the Department of Medicine and the Department of Psychiatry in Pitt's School of Medicine, and the Department of Epidemiology in Pitt's Graduate School of Public Health, with the success of the local clinical trials.

Participants were assigned randomly to the Intensive Lifestyle Intervention group or the Diabetes Support and Education group. Members of the Intensive Lifestyle Intervention group were enrolled in a weight management program that provided individual and group support for making changes in eating behaviors and engaging in physical activity. The intervention program focused on home-based, functional activities including helping participants balance, climb stairs, and get out of a chair, among other examples. Diabetes Support and Education group members received what Jakicic called "usual care, with some very infrequent support on general health topics that were not related to diet, physical activity, or weight loss."

Participants were required to have their own health care providers manage their diabetes and other conditions. Look AHEAD did not provide medical care, but it did assist participants in finding a health care provider if they did not have one.

The Look AHEAD study was intended to run for 13.5 years, the maximum length of time researchers had determined might be required to see a difference in heart disease between two groups. After 11 years, however, the Look AHEAD Data and Safety Monitoring Board, an independent monitoring board that provides recommendations to the National Institutes of Health, reviewed the data the study had collected and determined that Look AHEAD could reach the definite conclusion that there were no differences in cardiovascular disease rates between the study's two groups.

Speculating on the failure of weight loss to reduce the risk of cardiovascular disease, researchers suggested that even greater weight loss may be necessary to reduce cardiovascular risk in diabetes patients who are overweight or obese. They also suggested that by providing participants in both groups, and their health care providers, with annual feedback on the participants' blood pressure, lipids, and blood sugar control, the cardiovascular disease risks for all experiment participants may have been reduced at a comparable rate.

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Study Sheds Light On Molecular Basis For Metabolic Health And Disease

Inside each of us is our own internal timing device. It drives everything from sleep cycles to metabolism, but the inner-workings of this so-called "circadian clock" are complex, and the molecular processes behind it have long eluded scientists. But now, researchers at the Gladstone Institutes have discovered how one important protein falls under direct instructions from the body's circadian clock. Furthermore, they uncover how this protein regulates fundamental circadian processes - and how disrupting its normal function can throw this critical system out of sync.

In the latest issue of the Journal of Neuroscience, Gladstone Investigator Katerina Akassoglou, PhD, and her team reveal in animal models how the production of the p75 neurotrophin receptor (p75NTR) protein oscillates in time with the body's natural circadian clock - and how these rhythmic oscillations help regulate vital metabolic functions. This discovery underscores the widespread importance of p75NTR by offering insight into how the circadian clock helps maintain the body's overall metabolic health.

Virtually every organism on the planet - from bacteria to humans - has a circadian clock, a biological timing mechanism that oscillates with a period of about 24 hours and is coordinated with the cycle of day and night. And while it runs independent of external cues, it is influenced by the rhythms of light, temperature and food availability. Intriguingly, recent studies have also found a link between circadian clocks and metabolism.

"Important metabolic functions are also heavily influenced by circadian clocks, which is why activities such as chronic night-shift work - which can cause a misalignment of this clock - increase one's risk for metabolic and autoimmune diseases such as obesity, Type 2 diabetes, cancer and multiple sclerosis," said Dr. Akassoglou. Dr. Akassoglou is also a professor of neurology at the University of California, San Francisco, (UCSF) with which Gladstone is affiliated. "In this study, we pinpointed p75NTR as an important molecular 'link' between circadian clocks and metabolic health."

Originally, p75NTR was only thought to be active in the nervous system. Later studies found it to be active in many cell types throughout the body, suggesting that it impacts a variety of biological functions. Last year, Gladstone researchers discovered that p75NTR was present in the liver and in fat cells, and that it regulates glucose levels in the blood - an important metabolic process. Since these findings uncovered a link between p75NTR and metabolism, the research team tested - first in a petri dish and then in animal models - whether there was also a link between p75NTR and the circadian clock.

The team focused on two genes called Clock and Bmal1. These so-called "circadian regulator genes," and others like them, are found throughout the body. Their activity controls the body's circadian clock. The researchers wanted to see if there was a connection between these circadian genes and p75NTR.

"Our initial experiments revealed such a connection," recalls Gladstone Postdoctoral Fellow Bernat Baeza-Raja, PhD, the paper's lead author. "In individual cells, we saw that p75NTR production was controlled by Clock and Bmal1, which bind directly to the gene that codes for the p75NTR and start production of the protein."

But perhaps even more important than how p75NTR was produced was when. The team found that p75NTR production, like the circadian clock genes themselves, oscillated in a 24-hour cycle - in sync with the cells' natural circadian rhythm. Experiments in mouse models further supported these findings.

And when the team genetically modified a group of mice so that it lacked the circadian Clock gene, everything else fell out of sync. The circadian oscillation of p75NTR production was disrupted, and p75NTR levels dropped.

However, what was most fascinating, say the researchers, was how a drop in p75NTR levels then affected a variety of circadian clock systems. Specifically, the regular oscillations of other circadian genes in the brain and the liver became disrupted, as well as genes known to regulate glucose and lipid metabolism.

"The finding that a loss of p75NTR affected circadian and metabolic systems is strong evidence that this protein is intricately tied to both," said Life Sciences Institute Director Alan Saltiel, PhD, who is also a professor at the University of Michigan and was not involved in the study. "It will be fascinating to see what additional insight Dr. Akassoglou and her team will uncover as they continue to examine the role of p75NTR in circadian clocks and metabolic function."

"While these findings reveal p75NTR to be an important link between circadian clocks and metabolism, the system is complex, and there are likely other factors at play," said Dr. Akassoglou. "We are currently working to identify the relationship between the circadian clock, metabolism and the immune system, so that one day we could develop therapies to treat diseases influenced by circadian clock disruption - including not only obesity and diabetes, but also potentially multiple sclerosis and even Alzheimer's disease."

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Obese Women Who Skip Breakfast At Greater Risk For Insulin Resistance

Overweight women who skip breakfast experience acute, or rapid-onset, insulin resistance, a condition that, when chronic, is a risk factor for diabetes, a new study finds. The results, which were presented at The Endocrine Society's 95th Annual Meeting in San Francisco, suggest that regularly skipping breakfast over time may lead to chronic insulin resistance and thus could increase an individual's risk for type 2 diabetes.

"Our study found that acute insulin resistance developed after only one day of skipping breakfast," said the study's lead author, Elizabeth Thomas, MD, an endocrinology fellow at the University of Colorado School of Medicine in Aurora.

In insulin resistance, a person requires more insulin to bring their glucose, or blood sugar, into a normal range, she explained.

Thomas and co-workers studied nine nondiabetic women, with an average age of 29, who were overweight or obese. The study took place on two days about a month apart. Subjects were randomly assigned to receive either breakfast or no breakfast at the first visit and the opposite at the second visit. Four hours later, all subjects ate the same standardized lunch at each visit. They had blood samples taken every 30 minutes after lunch for three hours to test their insulin and glucose levels.

It is normal for glucose levels to rise after eating a meal, which then triggers insulin production. The researchers found, however, that the women's insulin and glucose levels after lunch were significantly higher on the day they skipped breakfast than on the day when participants ate breakfast. The higher levels demonstrated acute insulin resistance because of skipping breakfast, according to Thomas.

It was not clear if this "heightened metabolic response" was temporary or lasting, but it may contribute to the development of chronic insulin resistance, she said. When the body becomes permanently resistant to the effects of the hormone insulin, sugar builds up in the blood, which can lead to prediabetes and diabetes over time.

"This information should help health care providers in counseling patients as to why it is better to eat a healthy, balanced breakfast than to skip breakfast," Thomas said.

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