Obesity is a leading global health challenge, and weight loss is widely promoted to reduce the health risks associated with it. However, there is growing evidence that weight loss for older people doesn’t deliver the same health benefits as it does in younger adults – and, in some cases, it may even adversely affect brain health.
In a new study from Ben-Gurion University of the Negev (BGU) in Beersheba, scientists compared the effects of diet-induced obesity and subsequent weight loss in young adult and middle-aged mice. Both age groups restored normal blood glucose regulation during weight loss, suggesting that metabolic benefits are preserved across ages.
But in middle-aged mice, weight loss unexpectedly worsened sterile inflammation (not infected by pathogens) in the hypothalamus – a brain region that regulates appetite, energy balance, and many other vital functions. This neuroinflammation – observed both at the molecular level and through microscopic imaging of microglia (the brain’s immune cells) – persisted for several weeks before subsiding.
The study, titled, “Weight loss aggravates obesity-induced hypothalamic inflammation in mid-aged mice” has just been published in the journal GeroScience.
Although the consequences of this aggravated neuroinflammation remain uncertain and may even be required for the metabolic benefits to occur, these results raise concerns. Chronic or dysregulated inflammation in the brain has been linked to cognitive decline and neurodegenerative diseases such as Alzheimer’s disease. Therefore, these unexpected findings raise new questions about how weight loss at midlife may interact with brain health.
Not a simple copy-and-paste of what works in young adulthood
“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 at the Institute for Biotechnology in the Negev 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.”
Zemer’s research team worked with Prof. Assaf Rudich, a medically-trained bio-medical researcher at BGU’s department of clinical biochemistry and pharmacology who studies obesity and related diseases and led the study with BGU neuroimmunologist Prof. Alon Monsonego. The team aimed at understanding how changes in the biology of fat contribute to these conditions, which could include biologically damaging effects in tissues such as the liver and cells comprising adipose tissue.
Zemer worked with Dr. Alexandra Tsitrina, a Russian-born developmental biologist who was in charge of an imaging facility in the Koltzov Institute of Developmental Biology of the Russian Academy of Science in Moscow, and who came on aliyah three years ago with her husband.
“Our study characterizes the body’s adaptive response to weight loss through two complementary dimensions – molecular and structural,” Tsitrina said. “This high-end imaging by advanced microscopy and image analysis with advanced computational analysis enable detection of sensitive changes with potential health ramifications.”
Investigations of how a disease affects the body’s functions, obesity, and its complications have been promoted by studying rodent models. Yet, while losing excess weight is a major aim in the clinic, preclinical research has focused on the triggers, mechanisms, and consequences of weight gain, leaving the sequence/dynamics of changes during weight loss poorly described. This is an important gap of knowledge, the researchers wrote.
While neuroinflammation is an established response to both weight gain and aging, the hypothalamic neuroinflammatory early response to weight loss has remained unknown, particularly in middle age, Rudich told The Jerusalem Post.
Asked whether what was found in the mouse model was relevant to humans, he said that “we already have epidemiological data about weight gain and loss among people aged 50 to 65. Even when ruling out underlying disease in this age group, weight loss in middle-aged people, rather than weight gain, may be associated with increased mortality. Beyond 65, patients may have sarcopenia (age-related loss of muscle mass, strength, and function, leading to weakness, fatigue, balance problems) and osteoporosis that can be further worsened by weight loss.”
Another problem is that scientists who study fat mouse models use young mice, which are equivalent to human late teen/young adulthood, while obesity in humans is particularly prevalent among middle-aged men and women.
Although he has an MD degree, Rudich does research and doesn’t work as a physician. When asked whether he would advise obese middle-aged people to lose weight at a more gradual and slower rate, he responded: “Intuitively, I would say yes, but as a scientist, I can’t do that. It has to be scientifically proven. But they should carry out physical activity.
“Importantly, not all sterile inflammation in the body that is not caused by a pathogen is harmful; it is needed to regenerate tissues,” he said. “Thus, the impact of this weight-loss induced inflammation needs to be further studied, remaining open also to the possibility it is actually needed for recovery from obesity, such as for the restoration of normal blood glucose levels.
“Here, we questioned whether weight-loss induced, rapid restoration of [a normal concentration of glucose in the blood] is mediated by the resolution of hypothalamic microgliosis (in which the main immune cells of the central nervous system increase in number and activation in response to injury, disease, or other insults).”
Microgliosis is linked to a number of neurodegenerative diseases and neurological disorders) in middle-aged mice. Year-old mice were fed normal chow or a high-fat diet for eight weeks, and weight loss was induced by a two-week switch back to normal food. Key findings were compared to young (seven-week-old) mice. Middle-aged mice lost within 54% of their excess body weight within two weeks, significantly less than young mice (68%).
The researchers stressed the need for further studies to uncover the mechanisms behind this temporary-but-worrisome neuroinflammatory response. They said future research could help design strategies that preserve the benefits of weight loss while safeguarding brain health in midlife and beyond.