Unraveling the Biocircuitry of Obesity

Mouse neurons

Caption: Mouse neurons (purple), with their nuclei (blue) and primary cilia (green).
Credit: Yi Wang, Vaisse Lab, UCSF

Obesity involves the complex interplay of diet, lifestyle, genetics, and even the bacteria living in the gut. But there are other less-appreciated factors that are likely involved, and a new NIH-supported study suggests one that you probably never would have imagined: antenna-like sensory projections on brain cells.

The study in mice, published in the journal Nature Genetics [1], suggests these neuronal projections, called primary cilia, are a key part of a known “hunger circuit,” which receives signals from other parts of the body to control appetite. The researchers add important evidence in mouse studies showing that changes in the primary cilia can produce a short circuit, impairing the brain’s ability to regulate appetite and leading to overeating and obesity.

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Muscle Enzyme Explains Weight Gain in Middle Age

Woman weighing herself

Thinkstock/tetmc

The struggle to maintain a healthy weight is a lifelong challenge for many of us. In fact, the average American packs on an extra 30 pounds from early adulthood to age 50. What’s responsible for this tendency toward middle-age spread? For most of us, too many calories and too little exercise definitely play a role. But now comes word that another reason may lie in a strong—and previously unknown—biochemical mechanism related to the normal aging process.

An NIH-led team recently discovered that the normal process of aging causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies show it also slows down metabolism, making it more difficult to burn fat. To see if reducing DNA-PK levels might rev up the metabolism, the researchers turned to middle-aged mice. They found that a drug-like compound that blocked DNA-PK activity cut weight gain in the mice by a whopping 40 percent!

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Obesity Research: Study Shows Significant Benefits of Modest Weight Loss

5% weight lossFor the one in three American adults who are obese, recommendations to lose substantial amounts of weight through a combination of diet and exercise can seem daunting and, at times, hopeless. But a new study should come as encouraging news for all those struggling to lose the extra pounds: even a modest goal of 5 percent weight loss delivers considerable health benefits.

In the NIH-funded study, people with obesity who lost just 5 percent of their body weight—about 12 pounds on average—showed improvements in several risk factors for type 2 diabetes and heart disease. They also showed metabolic improvements in many parts of the body, including the liver, pancreas, muscle, and fat tissue. While people who lost additional weight enjoyed further improvements in their health, the findings reported in the journal Cell Metabolism show that sometimes it really does pay to start small [1].

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What Is Obesity? Metabolic Signatures Offer New Comprehensive View

Silhouettes over an NMR

Credit: Adapted from Elliott, P et al., Sci Transl Med. 2015 Apr 29;7(285)

As obesity has risen in the United States and all around the world, so too have many other obesity-related health conditions: diabetes, heart disease, stroke, cancer, and maybe even Alzheimer’s disease. But how exactly do those extra pounds lead to such widespread trouble, and how might we go about developing better ways to prevent or alleviate this very serious health threat?

In a new study in Science Translational Medicine [1], researchers performed sophisticated analyses of the molecules excreted in human urine to produce one of the most comprehensive pictures yet of the metabolic signature that appears to correlate with obesity. This work provides a fascinating preview of things to come as researchers from metabolomics, microbiomics, and a wide variety of other fields strive to develop more precise approaches to managing and preventing disease.

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Tracing the Neural Circuitry of Appetite

MC4R PVH neurons-the heart of hunger

Caption: A stylized image of the MC4R-expressing neurons (in red) within the brain’s PVH, which is the “heart of hunger”
Credit: Michael Krashes, NIDDK, NIH

If you’ve ever skipped meals for a whole day or gone on a strict, low-calorie diet, you know just how powerful the feeling of hunger can be. Your stomach may growl and rumble, but, ultimately, it’s your brain that signals when to start eating—and when to stop. So, learning more about the brain’s complex role in controlling appetite is crucial to efforts to develop better ways of helping the millions of Americans afflicted with obesity [1].

Thanks to recent technological advances that make it possible to study the brain’s complex circuitry in real-time, a team of NIH-funded researchers recently made some important progress in understanding the neural basis for appetite. In a study published in the journal Nature Neuroscience, the researchers used a variety of innovative techniques to control activity in the brains of living mice, and identified one particular circuit that appears to switch hunger off and on [2].

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