Research has found that obesity and mental disorders such as depression and
anxiety seem to often go hand in hand. Researchers at Baylor College of
Medicine and collaborating institutions are providing new insights into this
association by identifying and characterizing a novel neural circuit that
mediates the reciprocal control of feeding and psychological states in mouse
models.
Similar to human patients, mice that consumed a high-fat diet not only
became obese, but also anxious and depressed, a condition mediated by a
defective brain circuit. When the researchers genetically or
pharmacologically corrected specific disruptions they had observed within
this circuit, the mice became less anxious and depressed and later lost
excess body weight.
Interestingly, weight loss was not the result of lack of appetite, but of
the animals’ change of food preference. Before the treatment, the mice
naturally preferred to eat a high-fat diet, but after the treatment they
turned their preference toward a healthier diet with reduced fat and
abundant protein and carbohydrates. The findings, published in the journal
Molecular Psychiatry, for the first time, not only reveal a key regulatory
mechanism for coinciding obesity and mental disorders, but also suggest the
possibility of a pharmacological treatment.
“Reports indicate that 43% of adults with depression are obese and that
adults with mental illness are more likely to develop obesity than those who
are mentally healthy,” said corresponding author Dr. Qi Wu, a Pew Scholar
for Biomedical Sciences, Kavli Scholar and assistant professor in
pediatrics-nutrition at Baylor’s Children’s Nutrition Research Center.
“Factors such as hormonal dysregulation, genetic deficiency and inflammation
have been proposed to be involved in the connection between obesity and
mental disorders. Here we provide evidence that supports the involvement of
a neural component.”
To investigate the neuronal circuits that could be involved in reciprocally
regulating weight gain and depression or anxiety, the researchers provided
mice with a high-fat diet. As expected, the animals became obese. They also
developed anxiety and depression. In these mice, the team studied the
function of neuronal circuits.
“We discovered in normal mice that two groups of brain cells, dBNST and AgRP
neurons located in separate brain areas, form a circuit or connection to
each other by extending cellular projections,” said co-first author Dr.
Guobin Xia, postdoctoral associate in the Wu lab. “This newly discovered
circuit was malfunctioning in mice that were both obese and depressed.”
“Using genetic approaches, we identified specific genes and other mediators
that were altered and mediated the circuit’s malfunction in the obese and
depressed mice,” said co-first author Dr. Yong Han, postdoctoral associate
in the Wu lab.
“Importantly, genetically restoring the neural defects to normal eliminated
the high fat diet-induced anxiety and depression and also reduced body
weight,” Xia said. “We were surprised to see that the animals lost weight,
not because they lost their appetite, but because genetically-aided
readjustment of the mental states changed their feeding preference from
high-fat to low-fat food.”
“Keeping in mind translational applications of our findings to the clinic,
we investigated the possibility of restoring the novel circuit
pharmacologically,” Wu said. “We discovered that the combination of two
clinically-approved drugs, zonisamide and granisetron, profoundly reduced
anxiety and depression in mice and promoted weight loss by synergistically
acting upon two different molecular targets within our newly identified
brain circuit. We consider that our results provide convincing support for
further studies and future clinical trials testing the value of a cocktail
therapy combining zonisamide and granisetron (or a selection of their
derivatives) to treat metabolic-psychiatric diseases.”
Reference:
Xia G, Han Y, Meng F, et al. Reciprocal control of obesity and
anxiety–depressive disorder via a GABA and serotonin neural circuit.
Molecular Psychiatry. Published online March 26, 2021:1-17. doi:
10.1038/s41380-021-01053-w