Losing weight in midlife may have a hidden brain cost
Weight loss restored healthy metabolism in both young and mid-aged mice, but the brain told a different story. In mid-aged animals, slimming down actually worsened inflammation in a brain region tied to appetite and energy balance. While this inflammation eventually subsided, brain inflammation has been linked to cognitive decline and neurodegenerative disease. The results suggest that weight loss in midlife may not be as straightforward as once thought.
Obesity remains one of the most serious health challenges worldwide, and weight loss is often encouraged as a way to lower the risks tied to excess weight. But growing research suggests that the effects of weight loss may change with age. During midlife, losing weight may not always produce the same health benefits seen in younger adults and in some cases, it may also influence brain health.
In a new study from Ben-Gurion University of the Negev (BGU), researchers examined how diet-induced obesity and later weight loss affected young adult mice compared with mid-aged mice. In both groups, weight loss successfully restored healthy blood glucose control, showing that key metabolic improvements occur regardless of age. However, the scientists also observed an unexpected difference. In mid-aged mice, weight loss led to increased inflammation in the hypothalamus, a part of the brain involved in regulating appetite, energy use, and other essential functions.
Brain Inflammation Raises New Questions
This increase in brain inflammation was detected at the molecular level and through detailed microscopic imaging of microglia (the brain's immune cells). The inflammatory response lasted for several weeks before gradually declining. While the long-term effects of this response are still unclear and may even play a role in achieving metabolic improvements, the findings raise important concerns. Persistent or poorly regulated inflammation in the brain has been linked to memory problems and neurodegenerative conditions such as Alzheimer's. As a result, the study highlights new questions about how weight loss during midlife may interact with brain health.
Researchers Urge a More Nuanced View of Midlife Weight Loss
"Our findings show that losing weight in midlife is not a simple copy-and-paste of what works in young adulthood," said Alon Zemer, an M.D.-Ph.D. candidate and the first author of this paper. "Weight loss remains essential for restoring metabolic health in obesity, but we need to understand the impact of weight loss on the mid-age brain and ensure brain health is not compromised."
Dr. Alexandra Tsitrina added: "Our study characterizes the body's adaptive response to weight loss through two complementary dimensions -- molecular and structural. This high-end imaging by advanced microscopy and image analysis with advanced computational analysis enable detection of sensitive changes with potential health ramifications."
Next Steps for Protecting Brain Health
The research team stresses the importance of additional studies to better understand why this temporary but concerning brain inflammation occurs during midlife weight loss. Future work could help scientists develop approaches that maintain the metabolic advantages of weight loss while also protecting brain health as people age.
The study, titled, "Weight loss aggravates obesity-induced hypothalamic inflammation in mid-aged mice" was published in and supported by an internal grant at BGU (with the Ilse Katz Institute of Nanoscale Science and Technology), and grants from theUS-Israel Binational Science Foundation (Grant no. 2021083) and the Israel Science Foundation (Grant No. 194/24).