[ad_1]
The link between obesity and depression has long been known, but the mechanisms behind how one can cause the other are not understood. Studies in mice conducted by a research team led by the University of Glasgow showed how fatty acids consumed as part of a high fat diet (HFD) flowed through the bloodstream in the region of the hypothalamus. brain and directly influenced the signaling pathways associated with depression even before obesity develops. "We all know that a reduction in the consumption of fatty foods can have many beneficial effects on health, but our research suggests that it also promotes a happier disposition," commented the director. of research, George Baillie, Professor of Molecular Pharmacology.
Obese depressed patients are less likely to respond well to existing antidepressants, and the new findings also suggest potential targets for the development of antidepressants that may be more effective than current treatments for obese or overweight patients. The research, reported today in Translational psychiatry, demonstrated that reducing the expression of the gene coding for phosphodiesterase 4A (PDE4A) in mice was sufficient to protect animals against the onset of depression symptoms related to obesity.
"This is the first time we've seen the direct effects of a high-fat diet on areas of the brain marked by depression," Baillie said. "This research can begin to explain how and why obesity is related to depression and how we can potentially better treat patients with these conditions." The researchers presented their findings in an article titled "Dietary fats entering the brain can explain the link between obesity and depression."
Epidemiological and clinical studies have linked obesity to depression, but the way in which the two states may be causally related has not been understood, the researchers wrote. "Although a positive association between obesity and depression has been established, which one plays a causal role in the development of the other and what is the molecular mechanism (s) of this phenomenon? which remains unknown ". Overweight and / or obese depressed patients respond less well to antidepressants than normal weight individuals, suggesting that single molecular pathways of depression may be active in overweight and obese individuals.
While the complex neurobiology of depression involves different regions of the brain, the hypothalamus is involved in both depression and obesity, and cyclic AMP (cAMP) signaling would play a role essential in the pathophysiology and pharmacology of depression, the researchers explained. Current antidepressants are thought to have an impact on the cAMP signaling cascade, thereby increasing the activity of cAMP-dependent protein kinase A (PKA). "The phosphorylation of proteins by PKA regulates a wide variety of neuronal functions," the researchers added. A role of phosphodiesterase enzymes that degrade cAMP has also been suggested. "In depression, signaling via cAMP can be altered by nucleotide phosphodiesterases (PDE) … Among all PDEs, members of the PDE4 gene family play a major role in the regulation of cognition and depressive disorders. "
Collaborating with collaborators from the Institute of Pharmaceutical Sciences at King's College London and the Gladstone Institute of Neurological Diseases at the University of California at San Francisco, the team directed by the University of Glasgow has conducted a series of studies to study the impact of diet and obesity. on the development of depression. Their early studies demonstrated that mice fed a high-fat diet to induce obesity developed behaviors related to depression even before becoming obese. Depression is also developed in a mouse model genetically modified to become obese when it is fed normally.
Gene expression analyzes suggest that consumption of large amounts of fat is correlated with changes in the PKA signaling pathway in the hypothalamus. "The genes regulating the signaling pathway of PKA were significantly decreased after 8 weeks under HFD," the investigators wrote. "… the consumption of an HFD regulates the signaling pathway of PKA in the hypothalamus and could be responsible for the development of the phenotype analogous to depression induced by obesity in mice."
Subsequent analyzes also showed that dietary and genetic origin-induced obesity was associated with increased expression and activity of one form of the phosphodiesterase enzyme 4 ( PDE4), phosphodiesterase 4A5 in the hypothalamus. (In humans, the related enzyme is called PDE4A4.) Inactivation of the PDE4A mouse gene in diet-induced and genetic-induced obesity models prevented the development of depression, even though animals fed with HFD were still gaining weight. "… The loss of PDE4A protects mice from the phenotype of depression associated with obesity, despite similar weight gains in response to an MPH," the scientists said.
Hypotheses on the hypothesis that dietary fatty acids could somehow be involved in the hypothalamic depression-related signaling changes identified in mice fed with HFD, the team found that free fatty acids (FFA), and especially palmitic acid, accumulated in the fat diet hypothalamus Other analyzes in a neuronal cell line showed that palmitic acid suppressed the track of the PKA. The results collectively indicated that palmitic acid consumed as part of a high-fat diet accumulates in the hypothalamus and disrupts the hypothalamic functions by suppressing the cAMP / PKA signal by Activation of PDE4A.
"The present study reveals that the accumulation of different fatty acids in the hypothalamus alters the signaling of PKA, suggesting a potential mechanism of action of dietary fatty acids in the regulation of disorders of the body. mood, such as depression, via the PKA signaling pathway, "the authors concluded. "To the best of our knowledge, the present results are the first to show that the consumption of a HFD induces an influx of dietary fatty acids, especially in the hypothalamus, leading to an alteration of the cAMP / PKA signaling cascade. and this decrease in the PKA pathway may be behaviorally involved in the development of depression in mice. "
The authors suggest that their findings could also help guide the development of newer, more effective antidepressants in obese and overweight patients. "… Small molecules that selectively target the interaction of PDEs with free fatty acid receptors could represent a new generation of antidepressants with increased specificity for overweight and / or obese individuals."
"We often use fatty foods to comfort us because they taste great, but in the long run it will probably affect the mood in a negative way," commented Baillie. "Of course, if you feel weak, to feel better, you could offer more fat foods, which would consolidate negative feelings … understand the types of fats, such as palmitic acid, likely to penetrate into the brain. and affect key areas and signaling will give people more information on how their diet can potentially affect their mental health. "
[ad_2]
Source link