Obesity can lead to impaired learning, memory and cognitive decline, but the underlying mechanisms are not fully understood.
A new mouse study reveals how obesity disrupts key signaling pathways in the brain, and shows the potential of two diabetes drugs, semaglutide and empagliflozin, to counteract these effects.
Key Findings:
- Obesity impaired spatial learning and memory in mice on a high-fat diet.
- Obesity decreased phosphorylation of key calcium channel proteins involved in synaptic plasticity and cognition.
- The diabetes drugs semaglutide and empagliflozin increased phosphorylation of these proteins and improved cognitive deficits.
- The findings suggest these drugs may protect against obesity-related cognitive decline by targeting calcium signaling pathways in the brain.
Source: Front Pharmacol. 2023
The Growing Link Between Obesity and Cognitive Impairment
With obesity rates continuing to climb globally, understanding its impacts on the brain has become increasingly important.
A growing body of research shows that obesity can negatively impact cognitive function, including learning, memory, attention and executive function.
Obesity has been linked to accelerated cognitive aging and heightened risk for neurodegenerative diseases like Alzheimer’s.
But how excess weight may disrupt brain function remains unclear.
Elucidating the biological mechanisms involved is key to developing ways to prevent or treat obesity-related cognitive problems.
Researchers are investigating various pathways, from effects on brain structure to impacts on neurotransmission.
New findings from a mouse study provide insights into how obesity may impair signaling involved in learning and memory consolidation.
The results also reveal two common diabetes medications – semaglutide and empagliflozin – as having potential to counteract some of these effects by targeting key signaling proteins in the brain.
Examining Signaling Disruptions in Obese Mouse Brains
The study, conducted by researchers at Hebei General Hospital in China, aimed to probe obesity-related alterations in the brain’s phosphorylation signaling networks.
Phosphorylation, the addition of phosphate groups to proteins, is a fundamental process regulating many aspects of cell function.
The researchers utilized an advanced technique called four-dimensional label-free quantitative phosphoproteomics to compare phosphorylation patterns in the hippocampus – a brain region crucial for learning and memory – in mice fed normal and high-fat diets.
The high-fat diet successfully induced obesity, causing expected increases in body weight, blood glucose and lipid levels in the mice.
After 12 weeks on the high-fat diet, these obese mice exhibited impaired performance on spatial learning and memory tests compared to normal diet controls.
Phosphoproteomic analysis revealed key differences in hippocampal phosphorylation between the groups.
The obese mice showed markedly decreased phosphorylation of several proteins involved in synaptic plasticity and neuronal signaling.
Notably, phosphorylation was reduced for three subunits of voltage-gated calcium channels – CACNA1D, CACNA1A and CACNA1B – which play important roles in neurotransmitter release, neuronal excitability and long-term potentiation, key processes underlying learning and memory consolidation.
The researchers suggest this decreased calcium channel phosphorylation contributed to the cognitive deficits observed in the obese mice by disrupting synaptic plasticity and neurotransmission.
Semaglutide and Empagliflozin Target Calcium Signaling
After identifying obesity-related hippocampal signaling disruptions, the researchers evaluated two drugs currently used to treat diabetes for their potential to correct these effects – semaglutide and empagliflozin.
Semaglutide is an injectable synthetic analog of the human hormone GLP-1, which regulates appetite and food intake.
Empagliflozin is an oral medication that works by inhibiting a protein that normally reabsorbs glucose in the kidneys. Both lower blood glucose levels and have shown cardio-protective effects.
Importantly, recent evidence indicates these drugs can also benefit the brain.
Semaglutide has exhibited neuroprotective properties in animal models of Alzheimer’s disease and stroke.
And empagliflozin has improved cognitive function in models of diabetes and hypertension.
When obese mice were treated with semaglutide or empagliflozin for 12 weeks, both drugs improved performance on cognitive tests, suggesting protective effects against obesity-related learning and memory deficits.
Analysis of phosphorylation signaling pathways provided key insights into the mechanisms involved.
Treatment with either drug significantly increased phosphorylation of the same calcium channel subunits found to be hypo-phosphorylated in the obese mice.
This indicates the cognitive benefits of semaglutide and empagliflozin may stem from their ability to restore calcium signaling crucial for proper synaptic function and plasticity.
While previous research has focused on metabolic and vascular effects, these findings reveal a more direct neuroprotective role by targeting neuronal signaling pathways underlying cognition.
Potential Therapeutics for Obesity-Related Cognitive Decline?
This study provides important evidence that commonly prescribed diabetes medications could have protective cognitive effects that go beyond their glucose-lowering properties.
Given the pressing need for strategies to maintain cognitive health amid rising obesity rates, repurposing existing drugs represents a promising approach.
The researchers suggest clinical investigation of semaglutide and empagliflozin for this purpose is warranted.
However, there are some limitations to the research.
As a mouse study, the findings require further validation.
And while correlational, the data do not prove a direct causal relationship between altered calcium signaling and cognitive deficits.
Ongoing research can build on these discoveries to further elucidate obesity-related neuronal disruptions and effects of drug interventions.
Still, by providing novel insights into potential biological mechanisms, the findings make key contributions to understanding the links between obesity and cognition.
This knowledge could ultimately pave the way for targeted therapeutics to protect brain function in obese individuals.
As obesity rises globally, developing strategies to mitigate associated health risks is imperative across medical disciplines.
While drugs like semaglutide and empagliflozin were created to control diabetes, this research highlights their potential for a much broader purpose – preserving cognitive abilities for the growing population carrying excess weight.
References
- Study: Effect of semaglutide and empagliflozin on cognitive function and hippocampal phosphoproteomic in obese mice
- Authors: Xiaoyi Chen et al. (2023)
