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Examining the effects of weight gain and loss—multiple molecules at a time

In a controlled study of weight gain and loss, researchers have assembled a comprehensive molecular profile of dramatic changes that occur in humans during short periods of weight fluctuation. By using a variety of different analytical methods on a large scale, they collected more than 2 million measurements that provide a window into the dynamic nature of the molecular, metabolic, and gut bacterial changes in study participants during weight gain and loss. The team of scientists selected 23 men and women who volunteered for the study and were overweight or had moderate obesity. While none of the participants had diabetes, they differed in their levels of insulin sensitivity or insulin resistance. People who are insulin-resistant (IR) require greater amounts of insulin, a hormone made by the pancreas, to maintain blood glucose (sugar) levels than people who are insulin-sensitive (IS), and they are more likely to develop type 2 diabetes and associated complications later in life. Therefore, the researchers performed a weight gain/loss intervention on weight-matched individuals with different insulin-sensitivity profiles to identify specific molecules and signaling pathways that could be involved in weight-related insulin resistance. At the study’s onset, the investigators analyzed participants’ biological samples (blood and stool) and found that differences in protein levels and gut microbial populations already existed between IR and IS individuals. For example, IR individuals exhibited molecular markers for inflammation in their blood. Because people with type 2 diabetes are known to have inflammation, this could potentially be an early warning sign for future disease. All participants then went on a controlled, high-calorie diet for 30 days, during which time each individual consumed approximately 880 excess calories and gained an average of 6 pounds. With just this modest amount of weight gain, molecular markers for fat metabolism, inflammation, and, heart disease, increased in both IR and IS participants, potentially providing a biological explanation for the link between weight gain and heart failure. In addition, the researchers observed a dramatic increase in numbers of a type of gut bacteria known to protect against insulin resistance in response to weight gain in animal models, but this increase only occurred in IS individuals. The weight gain period was followed by a 60-day period of calorie restriction designed for participants to return to their original weight. Notably, most biomolecules, pathways, and microbes that were disrupted by weight gain returned to normal levels with weight loss, suggesting that deleterious effects of short-term, modest weight gain can be mitigated with dietary intervention. Some effects, however, continued post-weight loss, indicating some longer-lasting consequences of even a brief period carrying extra pounds.

Taken together, these results provide a dynamic picture of the human body’s molecular response to weight fluctuation and illustrate how even short-term periods of modest weight gain can affect metabolism, the gut microbiome, and heart health. Moreover, this research highlights the fact that individuals are unique at the molecular level and emphasizes the need for personalized analysis in medicine. Further studies with the publicly available data generated by this study could lead to personalized, predictive molecular signatures for type 2 diabetes and other weight-related conditions long before a disease manifests.

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