In a recent review published in European Journal of EndocrinologyIn this article, the researchers discussed current research on the relationship between human obesity and hypothalamic inflammation.
Stady: Is human obesity an inflammatory disease of the hypothalamus? Image credit: SciePro/Shutterstock
In 2022, the World Health Organization (WHO) declared that obesity was a pandemic in Europe, with 60% of the adult population obese or overweight. Obesity directly reduces longevity and also increases the risk of various other diseases such as cardiovascular disease, type 2 diabetes, hyperlipidemia, high blood pressure, gout, and various types of cancers.
Metabolic inflammation and its association with obesity is a research area that has received attention recently. Metabolic inflammation includes chronic, low-grade inflammation of peripheral tissues such as adipose tissue, liver, and hypothalamus. The hypothalamus is thought to be the center of the brain that regulates appetite and body weight. While hypothalamus has been studied in animal models and humans, recent research is examining whether hypothalamus may not be a consequence of obesity but rather a cause.
The arcuate nucleus of the medial hypothalamus integrates various factors from the peripheral endocrine glands and regulates appetite and satiety. Two groups of functionally opposite neurons are located in the arcuate nucleus. Y-peptide neurons and X-related peptide neurons form one group, and the lethal proopiomelanocortin group is transcriptionally and cocaine-regulated by cocaine and amphetamine, all four of these order I neurons are involved in the regulation of satiety and appetite. These neurons also express insulin and leptin receptors, which are directly related to nutrition and energy storage in the body.
Other digestive hormones such as glucagon-like peptide 1, ghrelin, and cholecystokinin can also stimulate neurons in the arcuate nucleus, mediating appetite and feelings of satiety.
Metabolic inflammation is the moderate and persistent overexpression of pro-inflammatory signals, which have been observed in adipose tissue, pancreas, liver and hypothalamus. Studies show that hypothalamus is triggered by various types of metabolic stimuli but not by body weight. Moreover, cells such as perivascular macrophages, astrocytes, microglia, and neurons are also involved in the initiation of chronic hypothalamus inflammation. Crosstalk between glial cells and astrocytes is believed to play a role in central nervous system (CNS) health and many CNS-related diseases.
Certain chemicals involved in the feedback between glial cells and astrocytes have been linked to obesity-related inflammation. In response to stimuli, microglia are thought to secrete pro-inflammatory signals that activate astrocytes. Since astrocytes express leptin and insulin receptors, continuous activation and feedback between astrocytes and glial cells affects energy homeostasis.
Studies in mouse models found that a hyperlipidemia diet was associated with impaired insulin signaling and the expression of inflammatory response proteins and cytokines in the hypothalamus. Other studies have also linked chronic high-fat diets to increased pro-inflammatory signals. Saturated fatty acids such as stearic acid, arachidic acid, and picnic acid are believed to significantly increase the secretion of pro-inflammatory mediators.
High-carb diets have also been linked to microglia activation and hypothalamic inflammation. While astrogliosis is primarily associated with fat metabolism and diets high in sucrose, hypothalamic inflammation was triggered in non-Astrogliosis rats, and a diet high in fructose has been shown to stimulate astrophysium and increase production of cytokines. Western diets are commonly thought to contain high amounts of saturated fatty acids and monosaccharides, and studies have found links between metabolic inflammation and Western diets and lifestyle. In addition, factors such as imbalances in the gut microbiome, age-related changes, and excessive nervous activity can be triggers of hypothalamus.
High-fat diets are thought to trigger hypothalamic inflammation through various signaling pathways, including toll-4-like receptors, c-Jun N-kinases, protein kinase C, ceramide pathways, and induction of endoplasmic reticulum stress.
A relaxation method involving T2-relaxation magnetic resonance imaging (MRI) was used to detect inflammation of the hypothalamus and glia in obese individuals. Postmortem biopsies also associated glia in the hypothalamus with higher BMI values.
Overall, the results indicated that hypothalamus could be a cause of obesity rather than simply a consequence. This is supported by the observation that the hypothalamus occurred even before weight gain following a high-fat diet. In addition, recent animal model research and translated human studies have demonstrated a link between hypothalamus inflammation and obesity. The development of MRI techniques for detecting hypothalamus could lead to targeting of pharmaceutical interventions for the treatment or management of obesity.