Inactivity in obese mice linked to a decreased motivation to move

Source: Cell Press
Date: 12/29/16
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Starting a regular program at the gym is a common New Year’s resolution, but it’s one that most people are unable to stick with for very long. Now a study done in mice is providing clues about one of the reasons why it may be hard for so many people to stick with an exercise program. The investigators found that in obese mice, physical inactivity results from altered dopamine receptors rather than excess body weight. The report appears in Cell Metabolism on December 29.

“We know that physical activity is linked to overall good health, but not much is known about why people or animals with obesity are less active,” says the study’s senior author Alexxai V. Kravitz, an investigator in the Diabetes, Endocrinology, and Obesity Branch at the National Institute of Diabetes and Digestive and Kidney Diseases–part of the National Institutes of Health. “There’s a common belief that obese animals don’t move as much because carrying extra body weight is physically disabling. But our findings suggest that assumption doesn’t explain the whole story.”

Kravitz has a background in studying Parkinson’s disease, and when he began conducting obesity research a few years ago, he was struck by similarities in behavior between obese mice and Parkinsonian mice. Based on that observation, he hypothesized that the reason the mice were inactive was due to dysfunction in their dopamine systems.

“Other studies have connected dopamine signaling defects to obesity, but most of them have looked at reward processing–how animals feel when they eat different foods,” Kravitz says. “We looked at something simpler: dopamine is critical for movement, and obesity is associated with a lack of movement. Can problems with dopamine signaling alone explain the inactivity?”

In the study, mice were fed either a standard or a high-fat diet for 18 weeks. Beginning in the second week, the mice on the unhealthy diet had higher body weight. By the fourth week, these mice spent less time moving and got around much more slowly when they did move. Surprisingly, the mice on high-fat diet moved less before they gained the majority of the weight, suggesting that the excess weight alone was not responsible for the reduced movements.

The investigators looked at six different components in the dopamine signaling pathway and found that the obese, inactive mice had deficits in the D2 dopamine receptor. “There are probably other factors involved as well, but the deficit in D2 is sufficient to explain the lack of activity,” says Danielle Friend, first author and former NIDDK postdoctoral fellow.

The team also studied the connection between inactivity and weight gain, to determine if it was causative. By studying lean mice that were engineered to have the same defect in the D2 receptor, they found that those mice did not gain weight more readily on a high-fat diet, despite their lack of inactivity, suggesting that weight gain was compounded once the mice start moving less.

“In many cases, willpower is invoked as a way to modify behavior,” Kravitz says. “But if we don’t understand the underlying physical basis for that behavior, it’s difficult to say that willpower alone can solve it.”

He adds that if we begin to decipher the physiological causes for why people with obesity are less active, it may also help reduce some of the stigma that they face. Future research will focus on how unhealthy eating affects dopamine signaling. The researchers also plan to look at how quickly the mice recover to normal activity levels once they begin eating a healthy diet and losing weight.

Diabetic mice on fasting-mimicking diet repair insulin-producing pancreas cells

Source: Cell Press
Date: 02/23/17
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Research in mice and human cells suggests that a fasting-mimicking diet may reprogram pancreas cells that are unable to produce insulin and enable them to repair themselves and start making it. The work, published February 23 in Cell, provides an alternative approach to replacing damaged insulin-producing beta cells.

“Our conclusion is that by pushing the mice into an extreme state and then bringing them back–by starving them and then feeding them again–the cells in the pancreas are triggered to use some kind of developmental reprogramming that rebuilds the part of the organ that’s no longer functioning,” says senior author Valter Longo of the University of Southern California School of Gerontology and Director of the USC Longevity Institute.

Longo originally developed the fasting-mimicking diet as a way to reduce stress and protect from toxicity in people undergoing chemotherapy. It involves consuming a very limited number of high-fat calories for five days and then returning to a normal diet. Measurement of four biomarkers associated with a water-only diet suggested that the diet has the same physiological effects on the body as more extreme fasting.

Studies since then have suggested that the diet may be a way to “reboot” the body by inducing it to slow down aging and regenerating new cells. Researchers have found that the expression of three key genes drops during the fasting-mimicking diet. These genes–IGF1, TOR, and PKA–are associated with stress and aging.

In the latest study, the researchers hypothesize that the downregulation of these three genes reprograms the cells so that they return to an embryonic-like state, in which they have the potential to give rise to a number of different cell types. “During starvation, the cells go into standby mode,” Longo says. “Then, when you begin refeeding the mice, you see these embryonic-like cells begin to give rise to beta cells.”

The researchers used two different mouse models of diabetes to study the effects of the diet. One was mice with a gene mutation that causes insulin resistance and loss of insulin secretion. The other was mice that were treated with a chemical to destroy their beta cells. Both models were given three cycles of the diet.

“Medically, these findings have the potential to be very important because we’ve shown–at least in mouse models–that you can use diet to reverse the symptoms of diabetes,” Longo says. “Scientifically, the findings are perhaps even more important because we’ve shown that you can use diet to reprogram cells without having to make any genetic alterations.” In addition to looking at mouse models of diabetes, the researchers also showed that exposure of human pancreatic islet cells–both from healthy donors and from patients with Type 1 diabetes–to fasting-mimicking diet in a dish stimulated insulin production.

Much research is needed before the findings can be validated in humans, but Longo says these clinical trials are already being planned. In Science Translational Medicine (DOI: 10.1126/scitranslmed.aai8700) on February 15, his team published a related, randomized Phase II study in 100 people that showed that when humans were exposed to three rounds of the fasting-mimicking diet, their IGF1 levels decreased and their fasting glucose levels improved, among other findings.

Longo says the findings also have implications for diseases beyond diabetes. “We want to start looking system by system to see how widely acting this process is on different types of cells,” he says. “The amazing thing is that this system has probably always been there. Now that we’ve discovered it, we can find ways to work with it and utilize it for benefits to human health.”