Abnormal Brain Development in Fetuses of Obese Women

In a study to be presented on February 15 between 8 a.m. and 10 a.m. PST, at the Society for Maternal-Fetal Medicine’s annual meeting, The Pregnancy Meeting ™, in San Francisco, California, researchers from Tufts Medical Center will present findings showing the effects of maternal obesity on a fetus, specifically in the development of the brain.

The study, conducted at the Mother Infant Research Institute (MIRI) at Tufts Medical Center in Boston, Mass., looked at the fetal development of 16 pregnant women, eight obese and eight lean, to see what effects maternal obesity had on fetal gene expression. Researchers have found that fetuses of obese women had differences in gene expression as early as the second trimester, compared to fetuses of women who were a healthy weight. Of particular note were patterns of gene expression suggestive of abnormal brain development in fetuses of obese women.

During gestation, fetuses go through apoptosis, a developmental process of programmed cell death. However, fetuses of the obese women were observed to have decreased apoptosis, which is an important part of normal fetal neurodevelopment. Dr. Diana Bianchi, senior author of the study and executive director of MIRI, describes apoptosis as a pruning process, clearing out space for new growth.

“Women won’t be surprised to hear being obese while pregnant can lead to obesity in the child,” said Dr. Andrea Edlow, lead author of the study and fellow in Maternal-Fetal Medicine at Tufts Medical Center. “But what might surprise them is the potential effect it has on the brain development of their unborn child.”

It is too early to know the implications of their findings, but maternal obesity is a rapidly growing problem in the U.S., with one in three women being obese at conception. The conclusion of the study points to the role of gene expression studies such as this one in helping elucidate possible mechanisms for recently-described postnatal neurodevelopmental abnormalities in children of obese women, including increased rates of autism and altered hypothalamic appetite regulation.

Old drug may point the way to new treatments for diabetes and obesity

Researchers at the University of Michigan’s Life Sciences Institute have found that amlexanox, an off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes and fatty liver in mice.

The findings from the lab of Alan Saltiel, the Mary Sue Coleman director of the Life Sciences Institute, were published online Feb. 10 in the journal Nature Medicine.

"One of the reasons that diets are so ineffective in producing weight loss for some people is that their bodies adjust to the reduced calories by also reducing their metabolism, so that they are ‘defending’ their body weight," Saltiel said. "Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice."

Different formulations of amlexanox are currently prescribed to treat asthma in Japan and canker sores in the United States. Saltiel is teaming up with clinical-trial specialists at U-M to test whether amlexanox will be useful for treating obesity and diabetes in humans. He is also working with medicinal chemists at U-M to develop a new compound based on the drug that optimizes its formula.

The study appears to confirm and extend the notion that the genes IKKE and TBK1 play a crucial role for maintaining metabolic balance, a discovery published by the Saltiel lab in 2009 in the journal Cell.

"Amlexanox appears to work in mice by inhibiting two genes—IKKE and TBK1—that we think together act as a sort of brake on metabolism," Saltiel said. "By releasing the brake, amlexanox seems to free the metabolic system to burn more, and possibly store less, energy."

Fighting fat with fat: stem cell discovery identifies potential obesity treatment

Ottawa scientists have discovered a trigger that turns muscle stem cells into brown fat, a form of good fat that could play a critical role in the fight against obesity. The findings from Dr. Michael Rudnicki’s lab, based at the Ottawa Hospital Research Institute, were published today in the prestigious journal Cell Metabolism.

"This discovery significantly advances our ability to harness this good fat in the battle against bad fat and all the associated health risks that come with being overweight and obese," says Dr. Rudnicki, a senior scientist and director for the Regenerative Medicine Program and Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute. He is also a Canada Research Chair in Molecular Genetics and professor in the Faculty of Medicine at the University of Ottawa.

Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.

Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.

In 2007, Dr. Rudnicki led a team that was the first to prove the existence of adult skeletal muscle stem cells. In the paper published today, Dr. Rudnicki now shows (again for the first time) that these adult muscle stem cells not only have the ability to produce muscle fibres, but also to become brown fat. Brown fat is an energy-burning tissue that is important to the body’s ability to keep warm and regulate temperature. In addition, more brown fat is associated with less obesity.

Perhaps more importantly, the paper identifies how adult muscle stem cells become brown fat. The key is a small gene regulator called microRNA-133, or miR-133. When miR-133 is present, the stem cells turn into muscle fibre; when reduced, the stem cells become brown fat.

Dr. Rudnicki’s lab showed that adult mice injected with an agent to reduce miR-133, called an antisense oligonucleotide or ASO, produced more brown fat, were protected from obesity and had an improved ability to process glucose. In addition, the local injection into the hind leg muscle led to increased energy production throughout the body—an effect observed after four months.

Using an ASO to treat disease by reducing the levels of specific microRNAs is a method that is already in human clinical trials. However, a potential treatment using miR-133 to combat obesity is still years away.

"While we are very excited by this breakthrough, we acknowledge that it’s a first step," says Dr. Rudnicki, who is also scientific director of the Stem Cell Network. "There are still many questions to be answered, such as: Will it help adults who are already obese to lose weight? How should it be administered? How long do the effects last? Are there adverse effects we have not observed yet?"

The brain circuit that makes it hard for obese people to lose weight

Imagine you are driving a car, and the harder you press on the accelerator, the harder an invisible foot presses on the brake. That’s what happens when obese people diet – the less food they eat, the less energy they burn, and the less weight they lose.

While this phenomenon is known, scientists at Sydney’s Garvan Institute of Medical Research and the University of NSW have pinpointed the exact brain circuitry behind it and have published their findings in the prestigious international journal Cell Metabolism, now online.

Dr Shu Lin, Dr Yanchuan Shi and Professor Herbert Herzog and his team have been studying the complex processes behind energy balance using various mouse models. They have shown that the neurotransmitter Neuropeptide Y (NPY), known for stimulating appetite, also plays a major role in controlling whether the body burns or conserves energy.

The researchers found that NPY produced in a particular region of the brain – the arcuate nucleus (Arc) of the hypothalamus – inhibits the activation of ‘brown fat’, one of the primary tissues where the body generates heat.

“This study is the first to identify the neurotransmitters and neural pathways that carry signals generated by NPY in the brain to brown fat cells in the body. It is also the first to show a direct connection between Arc NPY, the sympathetic nervous system and the control of energy expenditure.” said Professor Herzog.

“We know that NPY also influences other aspects of the sympathetic nervous system – such as heart rate and gut function – but its control of heat generation through brown fat seems to be the most critical factor in the control of energy expenditure.”

“When you don’t eat, or dramatically curtail your calorie intake, levels of NPY rise sharply. High levels of NPY signal to the body that it is in ‘starvation mode’ and should try to replenish and conserve as much energy as possible. As a result, the body reduces processes that are not absolutely necessary for survival.”

“Evolution has provided us with these mechanisms to help us survive famine, and they are strictly controlled. When people had to survive by finding food or hunting game, they could not afford to run out of energy and die of exhaustion, so their bodies evolved to cope.”

“Until the twentieth century, there were no fast food chains and people did not have ready access to high fat, high sugar, foods. So in evolutionary terms, it was unlikely that people were going to get very fat and mechanisms were only put in place to prevent you losing weight.”

“Obesity is a modern epidemic, and the challenge will be to find ways of tricking the body into losing weight – and that will mean somehow circumventing or manipulating this NPY circuit, probably with drugs.”

When food porn holds no allure: the science behind satiety

New research from the University of British Columbia is shedding light on why enticing pictures of food affect us less when we’re full.

“We’ve known that insulin plays a role in telling us we’re satiated after eating, but the mechanism by which this happens is unclear,” says Stephanie Borgland, an assistant professor in UBC’s Dept. of Anesthesiology, Pharmacology and Therapeutics and the study’s senior author.

In the new study published online this week in Nature Neuroscience, Borgland and colleagues found that insulin – prompted by a sweetened, high-fat meal – affects the ventral tegmental area (VTA) of the brain, which is responsible for reward-seeking behaviour. When insulin was applied to the VTA in mice, they no longer gravitated towards environments where food had been offered.

“Insulin dulls the synapses in this region of the brain and decreases our interest in seeking out food,” says Borgland, “which in turn causes us to pay less attention to food-related cues.”

“There has been a lot of discussion around the environmental factors of the obesity epidemic,” Borgland adds, pointing to fast food advertising bans in Quebec, Norway, the U.K., Greece and Sweden. “This study helps explain why pictures or other cues of food affect us less when we’re satiated – and may help inform strategies to reduce environmental triggers of overeating.”

The VTA has also been shown to be associated with addictive behaviours, including illicit drug use. Borgland says better understanding of the mechanism in this region of the brain could, in the long run, inform diagnosis and treatment.

(Image: Shutterstock)

Detrimental effect of obesity on lesions associated with Alzheimer’s disease

Researchers from Inserm and the Université Lille/Université Lille Nord de France have recently used a neurodegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. This research was conducted on mice and is published in the Diabetes review: it corroborates the theory that metabolic anomalies contribute massively to the development of dementia.

In France, more than 860,000 people suffer from Alzheimer’s disease and related disorders, making them the largest cause of age-related loss of intellectual function. Cognitive impairments observed in Alzheimer’s disease result from the accumulation of abnormal tau proteins in nerve cells undergoing degeneration (see the picture below). We know that obesity, a major risk factor in the development of insulin resistance and type 2 diabetes, increases the risk of dementia during the aging process. However, the effects of obesity on ‘Taupathies’ (i.e. tau protein-related disorders), including Alzheimer’s disease, were not clearly understood. In particular, researchers assumed that insulin resistance played a major role in terms of the effects of obesity.

The “Alzheimer & Tauopathies” team from mixed research unit 837 (Inserm/Université Lille 2/Université Lille Nord de France) directed by Dr. Luc Buée, in collaboration with mixed research unit 1011 “Nuclear receptors, cardiovascular diseases and diabetes”, have just demonstrated, in mice, that obese subjects develop aggravated disorders. To achieve this result, young transgenic mice, who develop tau-related neurodegeneration progressively with age, were put on a high-fat diet for five months, leading to progressive obesity.

“At the end of this diet, the obese mice had developed an aggravated disorder both from the point of view of memory and modifications to the Tau protein”, explains David Blum, in charge of research at Inserm.

This study uses a neurodenegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. Furthermore, it indicates that insulin resistance is not the aggravating factor, as was suggested in previous studies.

“Our research supports the theory that environmental factors contribute massively to the development of this neurodegenerative disorder” underlines the researcher. “Our work is now focussing on identifying the factors responsible for this aggravation” he adds.

Imaging Study Examines Effect of Fructose on Brain Regions That Regulate Appetite

In a study examining possible factors regarding the associations between fructose consumption and weight gain, brain magnetic resonance imaging of study participants indicated that ingestion of glucose but not fructose reduced cerebral blood flow and activity in brain regions that regulate appetite, and ingestion of glucose but not fructose produced increased ratings of satiety and fullness, according to a preliminary study published in the January 2 issue of JAMA.

“Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Fructose ingestion produces smaller increases in circulating satiety hormones compared with glucose ingestion, and central administration of fructose provokes feeding in rodents, whereas centrally administered glucose promotes satiety,” according to background information in the article. “Thus, fructose possibly increases food-seeking behavior and increases food intake.” How brain regions associated with fructose- and glucose-mediated changes in animal feeding behaviors translates to humans is not completely understood.

Kathleen A. Page, M.D., of Yale University School of Medicine, New Haven, Conn., and colleagues conducted a study to examine neurophysiological factors that might underlie associations between fructose consumption and weight gain. The study included 20 healthy adult volunteers who underwent two magnetic resonance imaging sessions in conjunction with fructose or glucose drink ingestion. The primary outcome measure for the study was the relative changes in hypothalamic (a region of the brain) regional cerebral blood flow (CBF) after glucose or fructose ingestion.

The researchers found that there was a significantly greater reduction in hypothalamic CBF after glucose vs. fructose ingestion. “Glucose but not fructose ingestion reduced the activation of the hypothalamus, insula, and striatum—brain regions that regulate appetite, motivation, and reward processing; glucose ingestion also increased functional connections between the hypothalamic-striatal network and increased satiety.”

“The disparate responses to fructose were associated with reduced systemic levels of the satiety-signaling hormone insulin and were not likely attributable to an inability of fructose to cross the blood-brain barrier into the hypothalamus or to a lack of hypothalamic expression of genes necessary for fructose metabolism.”

(Image: iStockphoto)

How Excess Holiday Eating Disturbs Your ‘Food Clock’

If the sinful excess of holiday eating sends your system into butter-slathered, brandy-soaked overload, you are not alone: People who are jet-lagged, people who work graveyard shifts and plain-old late-night snackers know just how you feel.

All these activities upset the body’s “food clock,” a collection of interacting genes and molecules known technically as the food-entrainable oscillator, which keeps the human body on a metabolic even keel. A new study by researchers at UCSF is helping to reveal how this clock works on a molecular level.

Published this month in the journal Proceedings of the National Academy of Sciences, the UCSF team has shown that a protein called PKCγ is critical in resetting the food clock if our eating habits change.

The study showed that normal laboratory mice given food only during their regular sleeping hours will adjust their food clock over time and begin to wake up from their slumber, and run around in anticipation of their new mealtime. But mice lacking the PKCγ gene are not able to respond to changes in their meal time – instead sleeping right through it.

The work has implications for understanding the molecular basis of diabetes, obesity and other metabolic syndromes because a desynchronized food clock may serve as part of the pathology underlying these disorders, said Louis Ptacek, MD, the John C. Coleman Distinguished Professor of Neurology at UCSF and a Howard Hughes Medical Institute Investigator.

It may also help explain why night owls are more likely to be obese than morning larks, Ptacek said.

“Understanding the molecular mechanism of how eating at the “wrong” time of the day desynchronizes the clocks in our body can facilitate the development of better treatments for disorders associated with night-eating syndrome, shift work and jet lag,” he added.

Resetting the Food Clock

Look behind the face of a mechanical clock and you will see a dizzying array of cogs, flywheels, reciprocating counterbalances and other moving parts. Biological clocks are equally complex, composed of multiple interacting genes that turn on or off in an orchestrated way to keep time during the day.

In most organisms, biological clockworks are governed by a master clock, referred to as the “circadian oscillator,” which keeps track of time and coordinates our biological processes with the rhythm of a 24-hour cycle of day and night.

Life forms as diverse as humans, mice and mustard greens all possess such master clocks. And in the last decade or so, scientists have uncovered many of their inner workings, uncovering many of the genes whose cycles are tied to the clock and discovering how in mammals it is controlled by a tiny spot in the brain known as the “superchiasmatic nucleus.”

Scientists also know that in addition to the master clock, our bodies have other clocks operating in parallel throughout the day. One of these is the food clock, which is not tied to one specific spot in the brain but rather multiple sites throughout the body.

The food clock is there to help our bodies make the most of our nutritional intake. It controls genes that help in everything from the absorption of nutrients in our digestive tract to their dispersal through the bloodstream, and it is designed to anticipate our eating patterns. Even before we eat a meal, our bodies begin to turn on some of these genes and turn off others, preparing for the burst of sustenance – which is why we feel the pangs of hunger just as the lunch hour arrives.

Scientist have known that the food clock can be reset over time if an organism changes its eating patterns, eating to excess or at odd times, since the timing of the food clock is pegged to feeding during the prime foraging and hunting hours in the day. But until now, very little was known about how the food clock works on a genetic level.

What Ptacek and his colleagues discovered is the molecular basis for this phenomenon: the PKCγ protein binds to another molecule called BMAL and stabilizes it, which shifts the clock in time.

Episodic Memory and Appetite Regulation in Humans

Psychological and neurobiological evidence implicates hippocampal-dependent memory processes in the control of hunger and food intake. In humans, these have been revealed in the hyperphagia that is associated with amnesia. However, it remains unclear whether ‘memory for recent eating’ plays a significant role in neurologically intact humans. In this study we isolated the extent to which memory for a recently consumed meal influences hunger and fullness over a three-hour period. Before lunch, half of our volunteers were shown 300 ml of soup and half were shown 500 ml. Orthogonal to this, half consumed 300 ml and half consumed 500 ml. This process yielded four separate groups (25 volunteers in each). Independent manipulation of the ‘actual’ and ‘perceived’ soup portion was achieved using a computer-controlled peristaltic pump. This was designed to either refill or draw soup from a soup bowl in a covert manner. Immediately after lunch, self-reported hunger was influenced by the actual and not the perceived amount of soup consumed. However, two and three hours after meal termination this pattern was reversed - hunger was predicted by the perceived amount and not the actual amount. Participants who thought they had consumed the larger 500-ml portion reported significantly less hunger. This was also associated with an increase in the ‘expected satiation’ of the soup 24-hours later. For the first time, this manipulation exposes the independent and important contribution of memory processes to satiety. Opportunities exist to capitalise on this finding to reduce energy intake in humans.