Modulation of mGluR5 expression in brain-gut axis: Relation to obesity

Objectives Obesity is mediated in part by alterations in central reward pathways and energy expenditure (EE). The metabotropic glutamate receptor, mGluR5, is a key modulator of reward-based feeding and its activation is associated with reduced EE. The presence of functional mGluR5 in the enteric nervous system suggests a role for this receptor in physiologic processes involving the brain-gut axis, such as energy regulation. To elucidate the role of mGluR function in obesity we investigated mGluR5 expression in the brain and gastrointestinal tract (GAT) of lean and obese rodents.

Methods We conducted studies in 6 male C57BL/6 mice (4 lean and 2 DIO) and 7 male Sprague Dawley rats (4 lean and 3 DIO). Lean animals were on a chow diet and DIO animals were on a 60% high-fat diet. All animals had PET imaging of mGluR5 expression using [18F]FPEB. Data were acquired in mice 30 min after ip administration of the ligand (80-116 µCi) for 60 min, while rats were imaged for 90 min (300-450 µCi i.v.). Regions of interest including striatum, hippocampus, cerebellum and the whole GAT area were determined. SUVs were determined at the time interval of 50-70 min using cerebellar data as reference.

Results In both mice and rats, mGluR5 expression was higher in the obese state compared to the lean state. In obese mice, mGluR5 expression was enhanced 24-52% in all brain areas compared to lean mice. Similarly, in the GAT, mGluR5 expression was 5-6 fold higher in the obese mice compared to the lean mice.The obese rats had only 3-7% higher expression of mGluR5 in the brain but 4-8 fold higher expression of mGluR5 in the GAT compared to lean rats. In all animals, mGluR5 expression in the GAT area was 8-11 fold higher than in the brain.

Conclusions Given that activation of mGluR5 is associated with increased food intake and reduced EE, our findings of increased expression of mGluR5 in the brain and gut of obese rodents suggests a role for the glutamate-mGluR5 neurotransmitter pathway in the pathogenesis of obesity.

Research Support NIBIB R01EB012864 to ALB NIMH R01MH91684 to ALB