Abstract
Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition to targets for the development of new drugs that can be used in humans to decrease body weight. Recently, sphingolipids were described as having a lipotoxic effect in peripheral tissues and the central nervous system. Specifically, lipid overload, mainly from long-chain saturated fatty acids, such as palmitate, leads to excessive ceramide levels that can be sensed by the hypothalamus, triggering the dysregulation of energy balance control. However, no systematic review has been undertaken regarding studies of sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), the hypothalamus, and obesity. This review confirms that ceramides are associated with hypothalamic dysfunction in response to metaflammation, endoplasmic reticulum (ER) stress, and lipotoxicity, leading to insulin/leptin resistance. However, in contrast to ceramide, S1P appears to be a central satiety factor in the hypothalamus. Thus, our work describes current evidence related to sphingolipids and their role in hypothalamic energy balance control. Hypothetically, the manipulation of sphingolipid levels could be useful in enabling clinicians to treat obesity, particularly by decreasing ceramide levels and the inflammation/endoplasmic reticulum stress induced in response to overfeeding with saturated fatty acids.
Highlights
IntroductionObesity has become a major public health issue, and an effective therapy has yet to be well established
The studies analyzed here monitored sphingolipid levels using different methodological approaches; it should be noted that RTq-PCR and WB are not suitable methods for ceramide quantification, and the results need additional interpretation
Ceramide accumulation in the hypothalamus causes inflammation, endoplasmic reticulum (ER) stress, and insulin/leptin resistance, interrupting the energy balance associated with an obese phenotype
Summary
Obesity has become a major public health issue, and an effective therapy has yet to be well established. Individuals who gain excess weight are at risk of developing chronic diseases, such as type 2 diabetes mellitus, cardiovascular diseases, and cancer [1,2]. Obese individuals were described as being more predisposed to developing severe symptoms of SARS-CoV-2, reinforcing to the scientific community that there is a need to improve the understanding of the pathophysiology of obesity and develop novel treatment strategies [3]. Excessive weight gain occurs when caloric consumption exceeds energy expenditure
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