There is at present a tremendous appetite for the development of novel pharmacological approaches to weight loss. This is in large part a response to the rising prevalence of obesity. No robustly proven answer exists as to the question of why exactly people are now becoming obese in such large numbers. There is no shortage of hypotheses, from excessive use of modern sugar substitutes to lack of exercise to specific widespread dietary additives to the presence of microplastics in the environment to changes in the average gut microbiome composition. The absence of a good answer and means of prevention means that efforts have turned to pharmacology for weight loss. This is not a new phenomenon, weight loss drugs have been greeted with enthusiasm since use of the mitochondrial uncoupler 2,4-dinitrophenol was pioneered in the early 20th century. The recent financial success of GLP-1 receptor agonists, that induce weight loss by suppressing appetite, has improved the prospects for any research efforts that can be in some way tied to producing weight loss.
So to the topic of today's open access paper, the effects of MT1-MMP in the aging brain. It appears that in parallel to effects on satiety and appetite, MT1-MMP also influences a range of mechanisms relevant to neurodegenerative conditions. Expression of MT1-MMP rises with age, perhaps driven by the chronic inflammation of aging, and this may be a useful target for the development of therapies. Interestingly, pharmacological inhibition of MT1-MMP activity restores some of the cognitive function lost to either aging or obesity when assessed in mice. Given that inhibition of MT1-MMP affects energy metabolism and produces weight loss, the balance of mechanisms involved in benefits produced in old mice versus obese mice may be quite different.
MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity
Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol.
Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity.
Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.
View the full article at FightAging
