Hypothalamic Fatty Acids and Ketone Bodies Sensing and Role of FAT/CD36 in the Regulation of Food Intake

Abstract

The obesity and type-2 diabetes epidemic is escalating and represents one of the costliest biomedical challenges confronting modern society. Moreover, the increasing consumption of high fat food is often correlated with an increase in body mass index. In people predisposed to be obese or already obese, the impaired ability of the brain to monitor and respond to alterations in fatty acid (FA) metabolism is increasingly recognized as playing a role in the pathophysiological development of these disorders. The brain senses and regulates metabolism using highly specialized nutrient-sensing neurons located mainly in the hypothalamus. The same neurons are able to detect variation in the extracellular levels of glucose, FA and ketone bodies as a way to monitor nutrient availability and to alter its own activity. In addition, glial cells such as astrocytes create major connections to neurons and form a tight relationship to closely regulate nutrient uptake and metabolism. This review will examine the different pathways by which neurons are able to detect free fatty acids (FFA) to alter its activity and how high fat diet (HFD)-astrocytes induced ketone bodies production interplays with neuronal FA sensing. The role of HFD-induced inflammation and how FA modulate the reward system will also be investigated here.

The fatty acid receptor CD36 promotes HCC progression through activating Src/PI3K/AKT axis-dependent aerobic glycolysis

“…CD36 is a central regulator for cell metabolism, maintaining lipid and glucose metabolism. The protein also transduces signaling to mediate its role in inflammation 33 , lipid metabolism, and insulin responsiveness, contributing to the pathogenesis of metabolic diseases, such as obesity, atherosclerosis, NAFLD, and type 2 diabetes 34 . The function of CD36 in fatty acid metabolism is well documented and several studies have revealed its association with cancer.…”

“…The function of CD36 in fatty acid metabolism is well documented and several studies have revealed its association with cancer. CD36-mediated exogenous fatty acid uptake and oxidation leads to cancer growth and metastasis 23 , 34 . Metabolic reprogramming has been recognized as a hallmark of cancer, changes of glucose, fatty acid, and glutathione metabolic pathways are often involved.…”

Metabolic regulation of neurodifferentiation in the adult brain

“…Besides glucose and lactate, ketone bodies represent an alternative fuel for neurons during fasting or extended exercise periods, reaching even 60-70% of the total energy supply for the brain [64]. Under low blood glucose levels adipocytes perform ketogenesis, releasing ketone bodies in the form of acetoacetate and b-hydroxybutyrate (BHB) into the bloodstream, which can cross the blood-brain barrier and be imported via MCT2 into neurons [65]. Additionally, unlike neurons, astrocytes are capable to perform ketogenesis providing with ketone bodies to neighbouring neurons [66].…”

Modulation of the Hypothalamic Nutrient Sensing Pathways by Sex and Early-Life Stress

“…As mentioned above, next to the hormonal regulation of food intake, circulating nutrients [e.g., glucose, fatty acids (FA)] are sensed in the hypothalamus and provide information about the energy state (Matzinger et al, 2000;Lam et al, 2005;Migrenne et al, 2006;Rijnsburger et al, 2016;Le Foll, 2019). More specifically, FA metabolism in the hypothalamus is suggested to function as sensor for nutrient/energy availability integrating both nutritional and hormonal signals.…”