The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review

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.

High-Fat Diet-Induced Mitochondrial Dysfunction Promotes Genioglossus Injury – A Potential Mechanism for Obstructive Sleep Apnea with Obesity

“… 39 Overaccumulation of FFAs could induce excessive ceramide levels, 40 which were reported to ultimately cause mitochondrial dysfunction and lipotoxicity. 41 , 42 In this study, we found that HFD-induced obesity led to mitochondrial damage; as the number of mitochondria decreased, they became swollen, and the cristae ruptured.…”

Hypothalamic CREB Regulates the Expression of Pomc-Processing Enzyme Pcsk2

“…Palmitate is one of the most important components of an HFD. It is also the predominant fatty acid consumed by humans [48][49][50]. Here, we showed that palmitate injected directly into the hypothalamus of mice promoted the increased activation of CREB, which predominantly occurred in Pomc neurons.…”

Ceramides in Autoimmune Rheumatic Diseases: Existing Evidence and Therapeutic Considerations for Diet as an Anticeramide Treatment

“…As most ceramides appear to be synthesized de novo, diet appears to be a major contributor to ceramide composition and the level of circulating ceramides in humans [ 174 ]. Fatty acids from the diet are expected to be reflected in the ceramide composition [ 175 , 176 ].…”