# Decreased CNS leptin activity in co-morbid depression and obesity

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

The overarching goal of this proposal is to demonstrate obesity-induced neuroinflammation in
the raphe nucleus decreases serotonin synthesis which decreases hippocampal serotonin levels,
thereby providing a neurochemical mechanism for co-morbid depressive illness in obesity.
 The incidence of obesity is greater in the VA population when compared with the general adult
US population, with current estimates suggesting that over 80% of Veterans may be classified as obese
or overweight. The complications of obesity extend to the central nervous system (CNS) and include an
increased risk of developing neuropsychiatric co-morbidities like depressive illness. Unfortunately, these
epidemiological studies cannot determine the neurochemical mechanism for this comorbidity. Clinical
studies provide some insight into this unanswered question in that obese individuals are more likely to
exhibit treatment resistance to serotonin selective uptake inhibitors (SSRIs) when compared to non-
obese individuals. Obesity is characterized by chronic mild inflammation and neuroinflammation has
been proposed to be responsible for decreases in serotonergic activity in co-morbid obesity and
depression. In spite of these advances, several critical questions remain to be addressed: 1) is
neuroinflammation increased in the raphe nucleus in obesity?; 2) does raphe nucleus neuroinflammation
decrease serotonin (5-HT) synthesis in the raphe nucleus and thereby decrease hippocampal 5-HT
levels? and 3) can we identify treatment strategies to reverse these changes and/or readily accessible
biomarkers that drive this comorbidity?
 Decreases in brain 5-HT levels are proposed to be a critical factor in the pathogenesis of
depressive illness. Interestingly, our ongoing studies suggest that hippocampal 5-HT levels are
significantly reduced in obese rats, thereby providing a potential neurochemical mechanism through
which obesity increases the risk of neuropsychiatric disorders. As the raphe nucleus is the primary site
of synthesis of 5-HT in the brain, neuroinflammation in the raphe nucleus may be a critical site for the
neurochemical deficits that drive depressive illness in obesity. In view of these observations, the
hypothesis of this proposal is that leptin resistance in the raphe nucleus decreases hippocampal
5-HT efflux, thereby providing a neurochemical mechanism for comorbid depressive illness in
obesity. This hypothesis will be tested in the following Aims.
 Aim 1 will determine whether neuroinflammation in the raphe nucleus decreases 5-HT synthesis and
 SSRI responses in the hippocampus of obese male and female rodents.
 Aim 2 will determine whether lifestyle interventions that are consistent with the VA MOVE! weight
 management program can reverse obesity-induced neuroinflammation, 5-HT deficits and depressive-
 like behaviors in obese rats.
Collectively, these studies will identify raphe nucleus neuroinflammation as the locus and neurochemical
mechanism for comorbid depressiv...

## Key facts

- **NIH application ID:** 10265411
- **Project number:** 5I01BX001804-08
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** LAWRENCE P REAGAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265411

## Citation

> US National Institutes of Health, RePORTER application 10265411, Decreased CNS leptin activity in co-morbid depression and obesity (5I01BX001804-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10265411. Licensed CC0.

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