Weight loss is often recommended as a cornerstone of better health, especially for people with obesity. But new research from Ben-Gurion University of the Negev suggests that the body’s response to weight loss may shift as we age and the brain could be part of the reason why.
In a study published in GeroScience, researchers compared how young adult and mid-aged mice responded to diet-induced obesity followed by weight loss. Both age groups regained normal blood glucose regulation once weight loss began. That finding reinforces what many studies have shown: losing weight still improves metabolic health, even later in life.
But the brain told a more complicated story. In mid-aged mice, weight loss triggered a surprising increase in inflammation within the hypothalamus, a small but critical region involved in appetite, energy balance and hormone signaling. This inflammation, visible both at the molecular level and through detailed imaging of microglia, the brain’s immune cells, lasted several weeks before gradually subsiding.
“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 study’s first author. “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.”
The team used molecular tools and advanced microscopy to examine how cells in the hypothalamus reacted during weight loss.
“Our study characterizes the body's adaptive response to weight loss through two complementary dimensions — molecular and structural,” said researcher Dr. Alexandra Tsitrina. “This high-end imaging by advanced microscopy and image analysis with advanced computational analysis enable detection of sensitive changes with potential health ramifications.”
Although the inflammation resolved on its own with time, its appearance raises important questions. Persistent or dysregulated inflammation in the hypothalamus has been linked in other research to cognitive decline and neurodegenerative diseases, including Alzheimer’s. The authors caution that it is too early to know whether this temporary spike in inflammation is harmful, beneficial or simply a normal adaptive response.
The study also highlights how much remains unknown about the aging brain’s relationship with weight loss. The metabolic benefits of losing weight were preserved in both young and mid-aged mice, yet the neurological response diverged. More work is needed to understand whether similar patterns may occur in humans and whether certain strategies, such as adjusting diet composition, timing or physical activity during weight loss, could help support brain health during midlife weight changes.
The researchers emphasize that the findings should not discourage weight loss in midlife. Instead, they point to a potential opportunity: developing weight loss approaches that support both metabolic benefits and long-term brain health.
This research was supported by internal funding from Ben-Gurion University of the Negev, the Ilse Katz Institute of Nanoscale Science and Technology, the US-Israel Binational Science Foundation and the Israel Science Foundation.