High-Fat Diet Linked to Anxiety, Depression

Liam Davenport

November 05, 2015

UPDATED November 9, 2015 // Consuming a high-fat diet may cause brain changes that lead to anxiety and depression, and although switching to a healthy diet reverses metabolic changes, mood problems persist, preliminary research suggests.

Results of the mouse study showed that a high-fat diet is linked to type 2 diabetes and anxiety and depression and that such a diet blunts the beneficial effect of antidepressants.

The research was led by Bruno P. Guiard, PhD, Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale, Toulouse, France, and Xavier Fioramonti, Center des Sciences du Goût et de l'Alimentation, Université de Bourgogne Franche-Comté, Dijon, France.

"There is a controversy regarding whether type-2 diabetes and major depression are causally linked," the investigators write. "Our present study provides clear-cut evidence, using an original approach based on the z-score method, that both pathologies are well correlated, notably when type-2 diabetes is induced by a prolonged high-fat diet.

"Considering the prevalence of type-2 diabetes and major depression, and their consequences on morbidity, mortality and quality of life, the optimization of current antidepressant treatment is highly required," they add.

The study was published online October 16 in the British Journal of Pharmacology.

Diabetes Link

For the study, investigators fed 30 mice a standard diet, a high-fat diet, or a 60% fructose-enriched diet for up 16 weeks. Body weight was monitored weekly.

The animals also underwent a comprehensive metabolic and behavioral analysis. A z-score was used to integrate the metabolic and behavioral data into single values.

Mice receiving the standard and high-fat diets were subcutaneously administered the selective serotonin reuptake inhibitor escitalopram for 4 weeks at the active dose.

As expected, the high-fat diet was associated with increased body weight, which was accompanied by fasting hyperglycemia, hyperinsulinemia, and glucose intolerance. The high-fructose diet was associated with the development of type 2 diabeteslike characteristics, although body weight did not increase.

The researchers found that there was a correlation between the development of metabolic symptoms and a high-fat diet and anxiogenic/depressionlike symptoms, which increased over time.

The high-fat diet was also associated with decreased levels of extracellular serotonin in the hippocampus, which the researchers suggest may result from increased sensitivity at the 5-HT1A autoreceptor.

Crucially, the anxiolytic/antidepressantlike effect of prolonged escitalopram administration seen in mice fed a standard diet was completely lost in mice given a high-fat diet, despite the drug's having no overall impact on metabolic parameters.

Persistent Effect on Mood

The team also found that although reinstatement of a standard diet for 1 month after 12 weeks of the high-fat diet reversed the weight gain and metabolic changes, there were persistent anxiogenic/depressionlike symptoms.

"Only treating the diabetes may not be sufficient to treat the anxiety. Maybe we have a stamp in the brain saying, 'Okay, we have a defect in the brain that is much stronger than any defect you can have in the periphery,' " Dr Fioramonti told Medscape Medical News while discussing these persistent behavioral problems following the high-fat diet.

More work is required before the findings can be translated to humans to show a direct link between diet and anxiety and depression. For example, Dr Fioramonti pointed out that the current study looked at only one strain of mice.

"We just wanted to do some preclinical studies here, trying to point out that, yes, there is a direct link between a high-fat diet and pathology, which is diabetes, and morbidity and some malbehavior issues, which can be anxiety," he said. "Now, can we translate that to humans? I don't know."

Future studies will need to focus on the molecular mechanisms underlying the relationship and to examine factors such as the role of polymorphisms and prior antidepressant therapy.

In humans, there are other issues that investigators face in such research, such as body weight changes and the psychological impact of being obese, which are not experienced by mice.

Nevertheless, Dr Fioramonti believes the current study has implications in terms of drug development.

"Let's say a new molecule would be developed by a company. Maybe they would be interested [in trying] their molecule in mice fed a standard diet but also a high-fat diet," he said.

"It could be very interesting for this company to show that their new molecule is efficient in any case, whether you are diabetic or not," he added.

Useful Study

Approached for comment, Felice N. Jacka, PhD, associate professor, Division of Nutritional Psychiatry Research, IMPACT Strategic Research Centre, Deakin University, Geelong, Australia, and president, International Society for Nutritional Psychiatry Research, said she believes it is a "very useful mechanistic study and may ― at least in part ― explain the interindividual responses to antidepressant treatments."

"It doesn't surprise me that they found the results they did with the high-fat diet. A high-fat diet induces gut dysbiosis and endotoxemia (leaky gut) in animal models, and the gut microbiota appear to be central in glucose regulation, insulin sensitivity, and other aspects of metabolism, as well as in mood and behavior," she added.

"As such, further research should examine whether the effects seen are mediated by changes in gut microbiota as a result of diet."

Dr Jacka was surprised that the high-fructose diet did not elicit the same behavioral responses seen with the high-fat diet.

"However, of course, mice are not human, and we must be cautious in extrapolating too much ― in humans, a high-fructose diet does increase body weight, so the mechanisms may not be the same," she said.

Dr Jacka also believes that although it was encouraging that withdrawal of the high-fat diet did lead to improvements in some behaviors, the follow-up period of 1 month may not have been long enough to determine whether a complete recovery would have occurred.

The study was supported by the Société Française du Diabète, BPG. One coauthor received funding through the National Council for Scientific and Technological Development. The other coauthors have disclosed no relevant financial relationships.

Br J Pharmacol. Published online October 16, 2015. Abstract

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