Chronic stress combined with fructose diet reduces hypothalamic insulin signaling and antioxidative defense in female rats.

<br>Background: Increased fructose consumption and chronic exposure to stress have been associated with development of obesity and insulin resistance. In the hypothalamus, a crossroad of stress response and energy balance, insulin and glucocorticoids regulate expression of orexigenic neuropeptides - neuropeptide Y (NPY) and agouti-related protein (AgRP) and anorexigenic neuropeptides - proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART).

OBJECTIVES: We investigated whether chronic stress and fructose diet disrupt these hormones' signaling pathways and appetite control in the hypothalamus, contributing to development of insulin resistance and obesity. Potential role of hypothalamic inflammation and oxidative stress in development of insulin resistance was also analyzed.

METHODS: Insulin, glucocorticoid and leptin signaling, expression of orexigenic and anorexigenic neuropeptides, and antioxidative and inflammatory status in the whole hypothalamus of fructose-fed female rats exposed to unpredictable stress for 9 weeks were analyzed using qPCR and Western blot.

RESULTS: Chronic stress combined with fructose-enriched diet reduced protein content and stimulatory phosphorylation of Akt kinase, and elevated 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor expression, while alterations in the appetite regulation (NPY, AgRP, POMC, CART, leptin receptor, and SOCS3 expression) were not observed. The expression of antioxidative defense enzymes (mitochondrial manganese superoxide dismutase 2, glutathione reductase and catalase) and proinflammatory cytokines (IL-1β, IL-6 and TNFα) was reduced.

CONCLUSIONS: Our results underline the combination of long-term stress exposure and fructose overconsumption as more detrimental for hypothalamic function than either of the factors separately, as it enhanced glucocorticoid and impaired insulin signaling, antioxidative defense and inflammatory response of this homeostasis-regulating center.<br>.