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Semaglutide & Empagliflozin May Treat Obesity-Related Cognitive Impairment (Mouse Study)

Obesity now affects over 650 million adults globally and is a major risk factor for various chronic diseases including cognitive decline and impairment.

Recent evidence shows a link between obesity, reduced brain volume and neuronal loss, increased dementia risk, and impaired learning, memory and cognition.

Preliminary evidence suggests that weight loss drugs like semaglutide may help treat obesity-induced cognitive impairment – independently of weight loss.


  • Study examined hippocampal protein expression differences in obese mice after semaglutide and empagliflozin treatment.
  • High-fat diet reduced phosphorylation of key calcium channel proteins involved in synaptic plasticity.
  • Semaglutide and empagliflozin increased phosphorylation of these proteins and improved cognitive function.
  • Findings suggest these drugs may help treat obesity-related cognitive decline by altering hippocampal dopamine signaling pathways.

Source: Frontiers in Pharmacology (2023)

Semaglutide & Empagliflozin in Obese Mice (Study Overview)

This study aimed to examine hippocampal phosphorylation protein expression differences in high-fat diet induced obese mice, with and without treatment by the anti-diabetic drugs semaglutide and empagliflozin, to elucidate signaling pathways involved in obesity-related cognitive impairment.

The findings provide insight into potential targeted treatments.

Methods: Evaluating Cognition & Drug Effects

32 male C57BL/6JC mice were randomized into control and high-fat diet groups for 12 weeks of feeding.

Obese mice were then treated with saline, semaglutide or empagliflozin for 12 more weeks before cognitive testing and hippocampal analysis.

Cognitive abilities were assessed using the Morris water maze spatial learning and memory test.

Blood samples were analyzed for metabolic markers.

Hippocampal phosphorylated proteins were evaluated using a 4D label-free quantitative phosphoproteomic technique and bioinformatic analysis.

Metabolic Effects of High-Fat Diet

As expected, the high-fat diet increased body weight, blood glucose, triglycerides, and cholesterol compared to controls.

Semaglutide and empagliflozin treatment partially reversed these metabolic effects.

Reversal of Cognitive Impairment with Drugs

Obese mice showed deficits in spatial learning and memory tasks compared to controls.

Both semaglutide and empagliflozin improved performance in cognitive testing, suggesting they can reverse obesity-related hippocampal functional decline.

Hippocampal Phosphoprotein Expression

Phosphoproteomic analysis identified over 20,000 phosphorylation sites on over 4,000 hippocampal proteins.

Many were involved in neuronal development, synaptic plasticity, axonogenesis, and dopamine signaling.

High-fat diet feeding significantly reduced phosphorylation of key calcium channel subunits CACNA1D, CACNA1A, and CACNA1B involved in the dopaminergic synapse pathway.

Semaglutide and empagliflozin increased phosphorylation of these same proteins.

(Related: Empagliflozin for Depression: Effective Adjunct to SSRIs)

Semaglutide & Empagliflozin May Treat Obesity-Induced Cognitive Deficits

This is the first study examining hippocampal phosphoproteomic differences after semaglutide and empagliflozin treatment in obese mice.

The findings suggest these drugs may improve obesity-induced cognitive deficits by altering dopamine neurotransmitter signaling pathways essential for synaptic plasticity and memory formation.

Specifically, reduced phosphorylation of the calcium channel proteins CACNA1D, CACNA1A and CACNA1B appears to be an important mechanism by which high-fat diets impair cognition.

These channels regulate calcium influx and dopamine release at synapses. Semaglutide and empagliflozin reversed the effects by increasing phosphorylation.

While semaglutide and empagliflozin are known to improve metabolic factors, these cognitive and molecular changes occurred independent of changes in body weight and blood glucose.

This highlights the potential broader neuroprotective properties of these drugs.

The study had several limitations. Combination treatment was not evaluated, the key pathway findings need further validation, and the causal relationship requires confirmation.

Overall this provides important groundwork highlighting new pathways for targeted treatment of obesity-associated cognitive decline using existing diabetes medications.

Takeaway: Semaglutide & Empagliflozin with Neuroprotective Effects vs. Obesity

In conclusion, this study found that a high-fat diet reduced phosphorylation of key calcium channel proteins CACNA1D, CACNA1A, and CACNA1B involved in the hippocampal dopaminergic synapse pathway, negatively impacting synaptic plasticity and cognition.

Semaglutide and empagliflozin were able to reverse these molecular changes and improve memory deficits, suggesting a potential new avenue for Alzheimer’s disease prevention and treatment.

Further research is warranted to confirm the mechanisms and translational potential of using these anti-diabetic medications to improve obesity-related cognitive impairment.


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