Using Intermittent Fasting as a Non-pharmacological Strategy to Alleviate Obesity-Induced Hypothalamic Molecular Pathway Disruption

Abstract

Intermittent fasting (IF) is a popular intervention used to fight overweight/obesity. This condition is accompanied by hypothalamic inflammation, limiting the proper signaling of molecular pathways, with consequent dysregulation of food intake and energy homeostasis. This mini-review explored the therapeutic modulation potential of IF regarding the disruption of these molecular pathways. IF seems to modulate inflammatory pathways in the brain, which may also be correlated with the brain-microbiota axis, improving hypothalamic signaling of leptin and insulin, and inducing the autophagic pathway in hypothalamic neurons, contributing to weight loss in obesity. Evidence also suggests that when an IF protocol is performed without respecting the circadian cycle, it can lead to dysregulation in the expression of circadian cycle regulatory genes, with potential health damage. In conclusion, IF may have the potential to be an adjuvant treatment to improve the reestablishment of hypothalamic responses in obesity.

Keywords: hypothalamic inflammation; hypothalamus; intermittent fasting (IF); non-pharmaceutical intervention; obesity.

FIGURE 1

Representative diagram of the interaction between anorectic hormones, molecular pathways, and neuropeptides POMC and AgRP. Anorexigenic hormones (leptin and insulin) act on the hypothalamic arcuate nucleus, reducing AMPK activation in AgRP neurons, thus reducing its expression. In POMC neurons, hormones increase mTOR activity and reduce AMPK, increasing its expression and reducing food intake and eutrophic phenotype.

FIGURE 2

Schematic model of the autophagic pathway. The process starts with activation of the ULK1 complex, then activation of phosphatidylinositol 3-kinase (PI3K), which forms a complex with Beclin 1 after it dissociates from lymphoma B cell 2 (BCL-2). Thus, the complex formed activates several proteins of the autophagic family (ATGs), which participate in the elongation of the phagophore and activation of the LC3-I protein (light chain 3 of protein 1 associated with microtubules), forming LC3-II, responsible for closing the phagophore and interacting with the p62 protein, signaling the material to be degraded. The phagophore matures into the autophagosome, which fuses with the lysosome forming the autolysosome, in which lysosomal enzymes will then degrade the sequestered material.

FIGURE 3

Schematic representation of the possible effects of intermittent fasting (IF) as an adjuvant treatment to partially rescue hypothalamic responses in obesity. Once IF prevents the pro-inflammatory effects in the hippocampus caused by LPS (29), and it is also able to increase the production of β-Hydroxybutyrate (βHB) (136), correlated to inflammatory control (134) and insulin sensitivity, it is possible to hypothesize that modulations in the microbiota may be helpful to reduce hypothalamic inflammation and increase hormonal sensitivity. Low serum leptin and insulin values during fasting contribute to an increase in the expression of AgRP and NPY. However, interestingly, the NPY mRNA expression returned to baseline values as a chronic response to IF, which may be is an adaptation to hunger. Furthermore, some studies found an increase in the expression of POMC neuropeptide, which is controversial. Such neuronal sensitivity to the IF protocol is perhaps also associated with better regulation of hypothalamic autophagic response since IF can activate the autophagic pathway in other tissues (146), and autophagic flux is an essential mediator of neuropeptide responses.