Abstract
Obesity is associated with an increased risk of depression. The aim of the present study was to investigate whether obesity is a causative factor for the development of depression and what is the molecular pathway(s) that link these two disorders. Using lipidomic and transcriptomic methods, we identified a mechanism that links exposure to a high-fat diet (HFD) in mice with alterations in hypothalamic function that lead to depression. Consumption of an HFD selectively induced accumulation of palmitic acid in the hypothalamus, suppressed the 3′, 5′-cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and increased the concentration of free fatty acid receptor 1 (FFAR1). Deficiency of phosphodiesterase 4A (PDE4A), an enzyme that degrades cAMP and modulates stimulatory regulative G protein (Gs)-coupled G protein-coupled receptor signaling, protected animals either from genetic- or dietary-induced depression phenotype. These findings suggest that dietary intake of saturated fats disrupts hypothalamic functions by suppressing cAMP/PKA signaling through activation of PDE4A. FFAR1 inhibition and/or an increase of cAMP signaling in the hypothalamus could offer potential therapeutic targets to counteract the effects of dietary or genetically induced obesity on depression.
Highlights
Obesity predominantly develops in response to increased consumption of energy-dense diets and a sedentary lifestyle[1]
Dietary-induced obesity (DIO) is accompanied by a depression-like phenotype in mice To determine whether the consumption of a fat-dense diet plays a causative role in the development of depression, we first examined depression-related behaviors among mice fed a highfat diet (HFD) for 3 or 8 weeks (Fig. 1a), where 60% of caloric intake is derived from fat
Consumption of an HFD was accompanied by the consumption of less sucrose solution than was observed for wild-type (WT) aged-matched control mice maintained on a normal diet (ND), a test related to anhedonia (Supplementary Fig. S1A), a characteristic feeling of depressed patients that describes their inability to experience pleasure by enjoyable activities
Summary
Obesity predominantly develops in response to increased consumption of energy-dense diets and a sedentary lifestyle[1]. Rare genetic mutations in the central melanocortin pathway are responsible for the development of monogenic obesity in humans[2]. The main clinical consequences of obesity are abnormalities characteristic of the metabolic syndrome (e.g., hypertension, insulin resistance, or dyslipidemia) and an increased risk of diseases such as cancer[3,4]. Obesity has been linked to depression[5,6], with both epidemiological and clinical studies demonstrating a positive association between these two disorders[7]. The neuropathophysiology of depression remains unclear, abnormalities in monoamine signaling components, such as serotonin and dopamine, have been implicated in the development of this condition[8]. Clinical observations around mid-90s suggested that depression results from decreased monoamine function in the brain[8]
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