High-fat diet with antibiotic use linked to gut inflammation

Combining Western diet and antibiotic use is a pre- IBD risk factor

July 15, 2020

Science Daily/University of California - Davis Health

UC Davis researchers have found that combining a Western-style high-fat diet with antibiotic use significantly increases the risk of developing pre-inflammatory bowel disease (pre-IBD). The study, published July 14 in Cell Host and Microbe, suggests that this combination shuts down the energy factories (mitochondria) in cells of the colon lining, leading to gut inflammation.

Irritable bowel syndrome (IBS) affects approximately 11% of people worldwide. It is characterized by recurring episodes of abdominal pain, bloating and changes in bowel habits. IBS patients with mucosal inflammation and changes in the gut's microbial composition are considered pre-IBD.

Antibiotic usage with high-fat diet is a risk factor

The study included 43 healthy adults and 49 adult patients diagnosed with IBS. The researchers measured fecal calprotectin, a biomarker for intestinal inflammation, of participants. Elevated levels of fecal calprotectin indicated a pre-IBD condition. The study identified 19 patients with IBS as pre-IBD.

The researchers found that all participants who consumed high-fat diet and used antibiotics were at 8.6 times higher risk for having pre-IBD than those on low-fat diet and no recent history of antibiotic use. Participants with the highest fat consumption were about 2.8 times more likely to have pre-IBD than those with the lowest fat intake. A history of recent antibiotic usage alone was associated with 3.9 times higher likelihood of having pre-IBD.

"Our study found that a history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD," said Andreas Bäumler, professor of medical microbiology and immunology and lead author on the study. "Until now, we didn't appreciate how different environmental risk factors can synergize to drive the disease."

Shutting the cell's powerhouse promotes gut microbial growth

Using mouse models, the study also tested the effect of high-fat diet and antibiotics use on the cells in the intestinal lining. It found that high-fat diet and antibiotics cooperate to disrupt the work of the cell's mitochondria, shutting its ability to burn oxygen. This disruption causes reduction in cell's oxygen consumption and leads to oxygen leakage into the gut.

The body's beneficial bacteria thrive in environments lacking oxygen such as the large intestine. Higher oxygen levels in the gut promote bacterial imbalances and inflammation. With the disruption in the gut environment, a vicious cycle of replacing the good bacteria with potentially harmful proinflammatory microbes that are more oxygen tolerant begins. This in turn leads to mucosal inflammation linked to pre-IBD conditions.

The study also identified 5-aminosalicylate (mesalazine), a drug that restarts the energy factories in the intestinal lining, as a potential treatment for pre-IBD.

"The best approach to a healthy gut is to get rid of the preferred sustenance of harmful microbes," Lee said. "Our study emphasized the importance of avoiding high fat food and abuse of antibiotics to avoid gut inflammation."

https://www.sciencedaily.com/releases/2020/07/200715142400.htm

Gut-brain connection helps explain how overeating leads to obesity

August 12, 2019

Science Daily/Baylor College of Medicine

A multi-institutional team reveals a previously unknown gut-brain connection that helps explain how those extra servings lead to weight gain.

Eating extra servings typically shows up on the scale later, but how this happens has not been clear. A new study published today in the Journal of Clinical Investigation by a multi-institutional team led by researchers at Baylor College of Medicine reveals a previously unknown gut-brain connection that helps explain how those extra servings lead to weight gain.

Mice consuming a high-fat diet show increased levels of gastric inhibitory polypeptide (GIP), a hormone produced in the gut that is involved in managing the body's energy balance. The study reports that the excess GIP travels through the blood to the brain where it inhibits the action of leptin, the satiety hormone; consequently, the animals continue eating and gain weight. Blocking the interaction of GIP with the brain restores leptin's ability to inhibit appetite and results in weight loss in mice.

"We have uncovered a new piece of the complex puzzle of how the body manages energy balance and affects weight," said corresponding author Dr. Makoto Fukuda, assistant professor of pediatrics at Baylor and the USDA/ARS Children's Nutrition Research Center at Baylor and Texas Children's Hospital.

Researchers know that leptin, a hormone produced by fat cells, is important in the control of body weight both in humans and mice. Leptin works by triggering in the brain the sensation of feeling full when we have eaten enough, and we stop eating. However, in obesity resulting from consuming a high-fat diet or overeating, the body stops responding to leptin signals -- it does not feel full, and eating continues, leading to weight gain.

"We didn't know how a high-fat diet or overeating leads to leptin resistance," Fukuda said. "My colleagues and I started looking for what causes leptin resistance in the brain when we eat fatty foods. Using cultured brain slices in petri dishes we screened blood circulating factors for their ability to stop leptin actions. After several years of efforts, we discovered a connection between the gut hormone GIP and leptin."

GIP is one of the incretin hormones produced in the gut in response to eating and known for their ability to influence the body's energy management. To determine whether GIP was involved in leptin resistance, Fukuda and his colleagues first confirmed that the GIP receptor, the molecule on cells that binds to GIP and mediates its effects, is expressed in the brain.

Then the researchers evaluated the effect blocking the GIP receptor would have on obesity by infusing directly into the brain a monoclonal antibody developed by Dr. Peter Ravn at AstraZeneca that effectively prevents the GIP-GIP receptor interaction. This significantly reduced the body weight of high-fat-diet-fed obese mice.

"The animals ate less and also reduced their fat mass and blood glucose levels," Fukuda said. "In contrast, normal chow-fed lean mice treated with the monoclonal antibody that blocks GIP-GIP receptor interaction neither reduced their food intake nor lost body weight or fat mass, indicating that the effects are specific to diet-induced obesity."

Further experiments showed that if the animals were genetically engineered to be leptin deficient, then the treatment with the specific monoclonal antibody did not reduce appetite and weight in obese mice, indicating that GIP in the brain acts through leptin signaling. In addition, the researchers identified intracellular mechanisms involved in GIP-mediated modulation of leptin activity.

"In summary, when eating a balanced diet, GIP levels do not increase and leptin works as expected, triggering in the brain the feeling of being full when the animal has eaten enough and the mice stop eating," Fukuda said. "But, when the animals eat a high-fat diet and become obese, the levels of blood GIP increase. GIP flows into the hypothalamus where it inhibits leptin's action. Consequently, the animals do not feel full, overeat and gain weight. Blocking the interaction of GIP with the hypothalamus of obese mice restores leptin's ability to inhibit appetite and reduces body weight."

These data indicate that GIP and its receptor in the hypothalamus, a brain area that regulates appetite, are necessary and sufficient to elicit leptin resistance. This is a previously unrecognized role of GIP on obesity that plays directly into the brain.

Although more research is needed, the researchers speculate that these findings might one day be translated into weight loss strategies that restore the brain's ability to respond to leptin by inhibiting the anti-leptin effect of GIP.

https://www.sciencedaily.com/releases/2019/08/190812160533.htm

High-fat diets affect your brain, not just your physical appearance

September 9, 2019

Science Daily/Yale University

Much research has pointed to how an unhealthy diet correlates to obesity, but has not explored how diet can bring about neurological changes in the brain. A recent Yale study has discovered that high-fat diets contribute to irregularities in the hypothalamus region of the brain, which regulates body weight homeostasis and metabolism.

Led by Sabrina Diano, the Richard Sackler Family Professor of Cellular & Molecular Physiology and professor of neuroscience and comparative medicine, the study evaluated how the consumption of a high-fat diet -- specifically diets that include high amounts of fats and carbohydrates -- stimulates hypothalamic inflammation, a physiological response to obesity and malnutrition.

The researchers reaffirmed that inflammation occurs in the hypothalamus as early as three days after consumption of a high-fat diet, even before the body begins to display signs of obesity. "We were intrigued by the fact that these are very fast changes that occur even before the body weight changes, and we wanted to understand the underlying cellular mechanism," said Diano who is also a member of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.

The researchers observed hypothalamic inflammation in animals on a high fat diet and discovered that changes in physical structure were occurring among the microglial cells of animals. These cells act as the first line of defense in the central nervous system that regulate inflammation. Diano's lab found that the activation of the microglia was due to changes in their mitochondria, organelles that help our bodies derive energy from the food we consume. The mitochondria were substantially smaller in the animals on a high-fat diet. The mitochondria's change in size was due to a protein, Uncoupling Protein 2 (UCP2), which regulates the mitochondria's energy utilization, affecting the hypothalamus' control of energy and glucose homeostasis.

The UCP2-mediated activation of microglia affected neurons in the brain that, when receiving an inflammatory signal due to the high fat diet, stimulated the animals in the high-fat diet group to eat more and become obese. However, when this mechanism was blocked by removing the UCP2 protein from microglia, animals exposed to a high fat diet ate less and were resistant to gain weight.

The study not only illustrates how high-fat diets affect us physically, but conveys how an unhealthy diet can alter our food intake neurologically. "There are specific brain mechanisms that get activated when we expose ourselves to specific type of foods. This is a mechanism that may be important from an evolutionary point of view. However, when food rich in fat and carbs is constantly available it is detrimental."

Diano's long-standing goal is to understand the physiological mechanisms that regulate how much food we consume, and she continues to perform research on how activated microglia can affect various diseases in the brain, including Alzheimer's disease, a neurological disorder that is associated with changes in the brain's microglial cells and has been shown to have higher incidence among obese individuals.

https://www.sciencedaily.com/releases/2019/09/190909121234.htm

Effects of a high-fat diet may be passed on for three generations

October 12, 2018

Science Daily/BioMed Central

A high-fat diet in female mice affects their offspring's obesity, insulin resistance and addictive-like behaviors for three generations, according to a new study.

Researchers at ETH Zurich, Switzerland showed that second generation offspring -- grandchildren of mice that had consumed a high-fat diet before, during and after pregnancy showed addictive-like behaviors such as increased sensitivity and preference for drugs, as well as characteristics of obesity, including changes in their metabolism. In third generation offspring (the great grandchildren), the authors observed differences between males and females, with only females showing addictive-like behaviors and only males showing obesity characteristics.

This was the case although the original female mice themselves never became obese and although none of the following generations consumed a high-fat diet.

Dr Daria Peleg-Raibstein, the corresponding author said: "Most studies so far have only looked at the second generation or followed the long-term effects of obesity and diabetes on the immediate offspring. This study is the first to look at the effects of maternal overeating up until the third generation in the context of addiction as well as obesity."

The authors investigated these effects specifically for transmission via male offspring up until, and including, the third generation. To do so, they fed female mice either high-fat diet or a standard laboratory diet for nine weeks -- pre-mating, during pregnancy and during lactation. Their male offspring were then mated with females that had been fed a standard laboratory diet to generate the second-generation offspring. The male offspring of these mice was again mated with females that had been fed a standard laboratory diet to generate the third-generation offspring.

The authors measured body weight, insulin sensitivity, metabolic rates, and blood plasma parameters such as insulin and cholesterol in second and third-generation offspring. In behavioral experiments they investigated if the mice chose a high-fat over a standard laboratory diet or an alcohol solution over water, as well as their activity levels after exposure to amphetamines. They did this to better understand if a maternal high-fat diet had an effect on obesity, overeating and drug sensitivity in subsequent generations.

Dr Peleg-Raibstein said: "To combat the current obesity epidemic, it is important to identify the underlying mechanisms and to find ways for early prevention. The research could help improve health advice and education for pregnant and breastfeeding couples and give their children, grandchildren and great-grandchildren a better chance of a healthy lifestyle. It may also provide a way of identifying risk factors for how people develop obesity and addiction and suggest early interventions for at-risk groups."

Dr Peleg-Raibstein added: "It is quite a leap to apply conclusions from mouse studies to humans, but studying effects of maternal over-eating is almost impossible to do in people because there are so many confounding factors, such as socio-economic background, the parents' food preferences or their existing health conditions. The mouse model allowed us to study the effects of a high-fat diet on subsequent generations without these factors."

Further studies are needed to determine the molecular mechanism by which the effects of a female high-fat diet may be passed on to following generations.

https://www.sciencedaily.com/releases/2018/10/181012082710.htm

Anti-inflammatory protein promotes healthy gut bacteria to curb obesity

New approach to weight loss and diabetes prevention published

September 19, 2018

Science Daily/University of North Carolina Health Care

Scientists have discovered that the anti-inflammatory protein NLRP12 normally helps protect mice against obesity and insulin resistance when they are fed a high-fat diet. The researchers also reported that the NLRP12 gene is underactive in people who are obese, making it a potential therapeutic target for treating obesity and diabetes, both of which are risk factors for cardiovascular disease and other serious conditions.

The study, published in Cell Host & Microbe, showed that NLRP12's anti-inflammatory effect promotes the growth of a "good" family of gut-dwelling bacteria, called Lachnospiraceae, that produce small molecules butyrate and propionate, which in turn promote gut health and protect mice against obesity and insulin resistance.

"Obesity is influenced by inflammation, not just by overeating and lack of exercise, and this study suggests that reducing inflammation promotes 'good' bacteria that can help maintain a healthy weight," said study senior author Jenny P-Y Ting, PhD, a William R. Kenan, Jr. Distinguished Professor of Genetics. "In mice, we showed that NLRP12 reduces inflammation in the gut and in adipose fat tissues. Although a direct causal effect is difficult to show in humans, our collaborators did help us show there are reduced expression levels of NLRP12 in individuals who are considered obese."

In humans, NLRP12 is produced by several types of immune cells and appears to function as a brake on excessive inflammation. Ting and colleagues in recent years have published studies showing that mice lacking the NLRP12 gene are highly susceptible to excessive inflammation, including experimental colon inflammation (colitis) and associated colon cancer.

In recent years, researchers have found evidence that inflammation in the gut and in where fat is deposited promotes obesity. About 40 percent of adults and 20 percent of children and teens age 2 to 19 in the United States are considered obese, according to recent government estimates. Being obese or even overweight can lead to a host of other conditions, including heart disease, stroke, cancers, and diabetes. Ting and colleagues in this study therefore sought to determine whether mice lacking the NLRP12 gene are more susceptible to obesity. The findings showed that they are.

The scientists fed mice that lacked the NLRP12 gene (NLRP12-knockout mice) and ordinary mice a high-fat diet for several months. The NLRP12-knockout mice ate and drank no more than their healthy cousins but accumulated significantly more fat and became heavier. The knockout mice also showed signs of insulin resistance, which involves a reduced ability to clear glucose from the bloodstream and tends to follow the development of obesity.

The absence of NLRP12 in these mice led to increased signs of inflammation in the gut and in fat deposits, but it wasn't clear how this led to extra weight gain until the researchers moved the animals from one facility to another. Following standard safety protocols to prevent disease spread, the researchers dosed the mice with antibiotics before the move.

"We noticed that the mice treated with antibiotics gained less weight than the mice that stayed in the old facility," said study co-first author Agnieszka Truax, PhD, a postdoctoral researcher in the Ting lab during the study. "That led us to suspect that gut bacteria were involved in promoting obesity."

Further tests showed that when NLRP12-knockout mice were kept in a bacteria-free condition, the mice did not gain weight because there were no bacteria. The deficiency of NLRP12 didn't matter as much. This suggested that "bad" bacteria had been driving the excess weight gain during a high-fat diet.

Remarkably, the knockout mice were also protected from excess weight gain when they were co-housed with control mice, hinting that "good" bacteria from the control mice were getting into them and helping to protect them.

Scientists have known that high-fat diets, as compared to low-fat diets, tend to reduce the diversity of bacterial species in the gut by suppressing some species and allowing a few others to proliferate abnormally. The UNC researchers confirmed this in their high-fat-eating mice, and they observed that the loss of bacterial diversity was much worse in the Nlrp12-knockout mice.

The experiments suggested that inflammation caused by a high-fat diet and worsened by the absence of NLRP12 was a major cause of this shift. Killing off rival bacterial species allowed a sharp rise in the levels of a bacterial family called Erysipelotrichaceae. These microbes became more prominent as gut inflammation worsened and exacerbated the weight-gain from a high-fat diet when put into the guts of otherwise germ-free mice.

By contrast, the Lachnospiraceae family of bacteria, which tended to die off in mice fed a high-fat diet, appeared to be highly beneficial. The researchers fed Lachnospiraceae to NLRP12-knockout mice prior to and during three weeks of high-fat eating and found that these "good" bacteria reduced gut inflammation, eliminated the hegemony of harmful Erysipelotrichaceae, and promoted more bacterial diversity. The Lachnospiraceae also significantly protected the animals against obesity and associated insulin-resistance.

"All the inflammatory and metabolic changes we had seen in the NLRP12-knockout mice during a high-fat diet were essentially reversed when we re-supplied Lachnospiraceae," Truax said.

Lachnospiraceae contain enzymes that convert carbs and fiber into small molecules called short-chain fatty acids (SCFAs). The scientists observed that two in particular, butyrate and propionate, appeared in significantly greater abundance when Lachnospiracea levels rose. Butyrate and propionate are known to have anti-inflammatory properties that promote gut health. The UNC team fed these SCFAs to the NLRP12-knockout mice and found that SCFAs protected the animals from the absence of NLRP12 just as well as the Lachnospiraceae had done.

Butyrate, propionate, and other SCFAs are already widely available as health supplements. But are these results in mice relevant to humans? A further test suggested that they are. Collaborating scientists Mihai Netea, MD, PhD, and Rinke Stienstra, PhD, from Radboud University Medical Center in the Netherlands examined fat cells from obese human patients and observed that the higher the measure of obesity -- the body-mass index -- the lower the activity of the NLRP12 gene tended to be.

Thus, treating people with "good" bacteria or the beneficial SCFAs they produce might one day be a relatively inexpensive strategy to combat obesity as well as diabetes and other obesity-driven conditions. Ting and colleagues plan to continue their investigations in that direction.

https://www.sciencedaily.com/releases/2018/09/180919133616.htm

Junk food almost twice as distracting as healthy food

October 26, 2017

Science Daily/Johns Hopkins University

When we haven't eaten, junk food is twice as distracting as healthy food or non-food items.

Even when people are hard at work, pictures of cookies, pizza and ice cream can distract them -- and these junk food images are almost twice as distracting as health food pictures, concludes a new Johns Hopkins University study, which also found that after a few bites of candy, people found junk food no more interesting than kale.

The study, which underscores people's implicit bias for fatty, sugary foods, and confirms the old adage that you shouldn't grocery shop hungry, is newly published online by the journal Psychonomic Bulletin and Review.

"We wanted to see if pictures of food, particularly high-fat, high-calorie food, would be a distraction for people engaged in a complicated task, said co-author Howard Egeth, a professor in the Department of Psychological and Brain Sciences. "So we showed them carrots and apples, and it slowed them down. We showed them bicycles and thumb tacks, and it slowed them down. But when we showed them chocolate cake and hot dogs, these things slowed them down about twice as much."

First, Egeth and lead author Corbin A. Cunningham, Distinguished Science of Learning Fellow in the Department of Psychological and Brain Sciences, created a complicated computer task, in which food was irrelevant, and asked a group of participants to find the answers as quickly as possible. As the participants worked diligently, pictures flashed in the periphery of the screen -- visible for only 125 milliseconds, which is too quick for people to fully realize what they just saw. The pictures were a mix of images of high-fat, high-calorie foods, healthy foods, or items that weren't food.

All of the pictures distracted people from the task, but Cunningham and Egeth found things like doughnuts, potato chips, cheese and candy were about twice as distracting. The healthy food pictures -- like carrots, apples and salads -- were no more distracting to people than non-foods like bicycles, lava lamps and footballs.

Next, the researchers recreated the experiment, but had a new group of participants eat two fun-sized candy bars before starting the computer work.

The researchers were surprised to find that after eating the chocolate, people weren't distracted by the high-fat, high-calorie food images any more than by healthy foods or other pictures.

The researchers wonder now if less chocolate or even other snacks would have the same effect.

"I assume it was because it was a delicious, high-fat, chocolatey snack," Egeth said. "But what if we gave them an apple? What if we gave them a zero-calorie soda? What if we told the subjects they'd get money if they performed the task quickly, which would be a real incentive not to get distracted. Could junk food pictures override even that?"

Cunningham said the results strikingly demonstrate that even when food is entirely irrelevant, and even when people think they're working hard and concentrating, food has the power to sneak in and grab our attention -- at least until we eat a little of it.

"What your grandmother might have told you about not going to the grocery store hungry seems to be true," Cunningham said. "You would probably make choices that you shouldn't or ordinarily wouldn't."

https://www.sciencedaily.com/releases/2017/10/171026135327.htm

Weight Gain Induced by High-Fat Diet Increases Active-Period Sleep

July 10, 2012

Science Daily/Society for the Study of Ingestive Behavior

Research presented at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB) finds that prolonged exposure to a high-fat diet reduces the quality of sleep in rats.

Using radio-telemetry, the authors measured 24-hour sleep and wake states after rats consumed a high fat diet for 8 weeks. Compared to rats that consumed a standard laboratory chow, the rats on the high-fat diet slept more but sleep was fragmented. The increased sleep time of the rats on the high-fat diet occurred mainly during the normally active phase of the day, resembling excessive daytime sleepiness observed in obese humans.

According to lead author, Catherine Kotz, "Studies in humans indicate a relationship between sleep quality and obesity. Our previous work in animals shows a link between good quality sleep, resistance to weight gain and increased sensitivity to orexin, a brain chemical important in stabilizing sleep and wake states. The current studies show that after high-fat diet-induced weight gain in rats, sleep quality is poor and orexin sensitivity is decreased. These findings suggest that poor sleep associated with weight gain due to a high-fat diet may be a consequence of reduced orexin sensitivity."

These studies highlight the impact of weight gain on sleep quality and a potential brain mechanism underlying these diet and weight-gain induced changes in sleep behavior.

http://www.sciencedaily.com/releases/2012/07/120710093804.htm

Another Reason to Avoid High-Fat Diet: It Can Disrupt Our Biological Clock

December 31, 2008

Science Daily/Hebrew University of Jerusalem

Indulgence in a high-fat diet can not only lead to overweight because of excessive calorie intake, but also can affect the balance of circadian rhythms – everyone’s 24-hour biological clock, Hebrew University of Jerusalem researchers have shown.

The biological clock regulates the expression and/or activity of enzymes and hormones involved in metabolism, and disturbance of the clock can lead to such phenomena as hormone imbalance, obesity, psychological and sleep disorders and cancer.

While light is the strongest factor affecting the circadian clock, Dr. Oren Froy and his colleagues of the Institute of Biochemistry, Food Science and Nutrition at the Hebrew University’s Robert H. Smith Faculty of Agriculture, Food and Environment in Rehovot, have demonstrated in their experiments with laboratory mice that there is a cause-and-effect relation between diet and biological clock imbalance.

To examine this thesis, Froy and his colleagues, Ph.D. student Maayan Barnea and Zecharia Madar, the Karl Bach Professor of Agricultural Biochemistry, tested whether the clock controls the adiponectin signaling pathway in the liver and, if so, how fasting and a high-fat diet affect this control. Adiponectin is secreted from differentiated adipocytes (fat tissue) and is involved in glucose and lipid metabolism. It increases fatty acid oxidation and promotes insulin sensitivity, two highly important factors in maintaining proper metabolism.

The researchers fed mice either a low-fat or a high-fat diet, followed by a fasting day, then measured components of the adiponectin metabolic pathway at various levels of activity. In mice on the low-fat diet, the adiponectin signaling pathway components exhibited normal circadian rhythmicity. Fasting resulted in a phase advance. The high-fat diet resulted in a phase delay. Fasting raised and the high-fat diet reduced adenosine monophosphate-activated protein kinase (AMPK) levels. This protein is involved in fatty acid metabolism, which could be disrupted by the lower levels.

In an article soon to be published by the journal Endocrinology, the researchers suggest that this high-fat diet could contribute to obesity, not only through its high caloric content, but also by disrupting the phases and daily rhythm of clock genes. They contend also that high fat-induced changes in the clock and the adiponectin signaling pathway may help explain the disruption of other clock-controlled systems associated with metabolic disorders, such as blood pressure levels and the sleep/wake cycle.

http://www.sciencedaily.com/releases/2008/12/081228191054.htm

Smelling your food makes you fat

Mice that lost sense of smell stayed slim on high fat diet, while littermates ballooned in weight

July 5, 2017

Science Daily/University of California - Berkeley

Researchers developed ways to temporarily eliminate the sense of smell in adult mice, and discovered that those mice that lost smell could eat a high-fat diet and stay a normal weight, while littermates that retained the sense of smell ballooned to twice normal weight. Supersmellers gained more weight than did normal mice on the same high-fat diet. Smell-deficient mice burned excess fat instead of storing it, suggesting a link between smell and metabolism.

Our sense of smell is key to the enjoyment of food, so it may be no surprise that in experiments at the University of California, Berkeley, obese mice who lost their sense of smell also lost weight.

What's weird, however, is that these slimmed-down but smell-deficient mice ate the same amount of fatty food as mice that retained their sense of smell and ballooned to twice their normal weight.

In addition, mice with a boosted sense of smell -- super-smellers -- got even fatter on a high-fat diet than did mice with normal smell.

The findings suggest that the odor of what we eat may play an important role in how the body deals with calories. If you can't smell your food, you may burn it rather than store it.

These results point to a key connection between the olfactory or smell system and regions of the brain that regulate metabolism, in particular the hypothalamus, though the neural circuits are still unknown.

"This paper is one of the first studies that really shows if we manipulate olfactory inputs we can actually alter how the brain perceives energy balance, and how the brain regulates energy balance," said Céline Riera, a former UC Berkeley postdoctoral fellow now at Cedars-Sinai Medical Center in Los Angeles.

Humans who lose their sense of smell because of age, injury or diseases such as Parkinson's often become anorexic, but the cause has been unclear because loss of pleasure in eating also leads to depression, which itself can cause loss of appetite.

The new study, published this week in the journal Cell Metabolism, implies that the loss of smell itself plays a role, and suggests possible interventions for those who have lost their smell as well as those having trouble losing weight.

"Sensory systems play a role in metabolism. Weight gain isn't purely a measure of the calories taken in; it's also related to how those calories are perceived," said senior author Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research, professor of molecular and cell biology and Howard Hughes Medical Institute Investigator. "If we can validate this in humans, perhaps we can actually make a drug that doesn't interfere with smell but still blocks that metabolic circuitry. That would be amazing."

Riera noted that mice as well as humans are more sensitive to smells when they are hungry than after they've eaten, so perhaps the lack of smell tricks the body into thinking it has already eaten. While searching for food, the body stores calories in case it's unsuccessful. Once food is secured, the body feels free to burn it.

Zapping olfactory neurons

The researchers used gene therapy to destroy olfactory neurons in the noses of adult mice but spare stem cells, so that the animals lost their sense of smell only temporarily -- for about three weeks -- before the olfactory neurons regrew.

The smell-deficient mice rapidly burned calories by up-regulating their sympathetic nervous system, which is known to increase fat burning. The mice turned their beige fat cells -- the subcutaneous fat storage cells that accumulate around our thighs and midriffs -- into brown fat cells, which burn fatty acids to produce heat. Some turned almost all of their beige fat into brown fat, becoming lean, mean burning machines.

In these mice, white fat cells -- the storage cells that cluster around our internal organs and are associated with poor health outcomes -- also shrank in size.

The obese mice, which had also developed glucose intolerance -- a condition that leads to diabetes -- not only lost weight on a high-fat diet, but regained normal glucose tolerance.

On the negative side, the loss of smell was accompanied by a large increase in levels of the hormone noradrenaline, which is a stress response tied to the sympathetic nervous system. In humans, such a sustained rise in this hormone could lead to a heart attack.

Though it would be a drastic step to eliminate smell in humans wanting to lose weight, Dillin noted, it might be a viable alternative for the morbidly obese contemplating stomach stapling or bariatric surgery, even with the increased noradrenaline.

"For that small group of people, you could wipe out their smell for maybe six months and then let the olfactory neurons grow back, after they've got their metabolic program rewired," Dillin said.

Dillin and Riera developed two different techniques to temporarily block the sense of smell in adult mice. In one, they genetically engineered mice to express a diphtheria receptor in their olfactory neurons, which reach from the nose's odor receptors to the olfactory center in the brain. When diphtheria toxin was sprayed into their nose, the neurons died, rendering the mice smell-deficient until the stem cells regenerated them.

Separately, they also engineered a benign virus to carry the receptor into olfactory cells only via inhalation. Diphtheria toxin again knocked out their sense of smell for about three weeks.

In both cases, the smell-deficient mice ate as much of the high-fat food as did the mice that could still smell. But while the smell-deficient mice gained at most 10 percent more weight, going from 25-30 grams to 33 grams, the normal mice gained about 100 percent of their normal weight, ballooning up to 60 grams. For the former, insulin sensitivity and response to glucose -- both of which are disrupted in metabolic disorders like obesity -- remained normal.

Mice that were already obese lost weight after their smell was knocked out, slimming down to the size of normal mice while still eating a high-fat diet. These mice lost only fat weight, with no effect on muscle, organ or bone mass.

The UC Berkeley researchers then teamed up with colleagues in Germany who have a strain of mice that are supersmellers, with more acute olfactory nerves, and discovered that they gained more weight on a standard diet than did normal mice.

"People with eating disorders sometimes have a hard time controlling how much food they are eating and they have a lot of cravings," Riera said. "We think olfactory neurons are very important for controlling pleasure of food and if we have a way to modulate this pathway, we might be able to block cravings in these people and help them with managing their food intake."

https://www.sciencedaily.com/releases/2017/07/170705123007.htm