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Review
. 2019 Aug;20(8):552-570.
doi: 10.1111/tra.12670. Epub 2019 Jun 24.

Metabolic regulation through the endosomal system

Jerome Gilleron  1 , Jantje M Gerdes  2   3 , Anja Zeigerer  3   4   5
Affiliations
Review

Metabolic regulation through the endosomal system

Jerome Gilleron et al. Traffic. 2019 Aug.

Abstract

The endosomal system plays an essential role in cell homeostasis by controlling cellular signaling, nutrient sensing, cell polarity and cell migration. However, its place in the regulation of tissue, organ and whole body physiology is less well understood. Recent studies have revealed an important role for the endosomal system in regulating glucose and lipid homeostasis, with implications for metabolic disorders such as type 2 diabetes, hypercholesterolemia and non-alcoholic fatty liver disease. By taking insights from in vitro studies of endocytosis and exploring their effects on metabolism, we can begin to connect the fields of endosomal transport and metabolic homeostasis. In this review, we explore current understanding of how the endosomal system influences the systemic regulation of glucose and lipid metabolism in mice and humans. We highlight exciting new insights that help translate findings from single cells to a wider physiological level and open up new directions for endosomal research.

Keywords: diabetes; endocytosis; fatty liver disease; glucose and lipid metabolism; metabolic signaling; nutrient transport.

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Figures

Figure 1
Figure 1
Involvement of endocytic components in systemic metabolism in the postprandial (feeding) period. After a meal, circulating blood glucose levels rise, leading to a massive entry of glucose into pancreatic β‐cells via the glucose transporter GLUT2, which causes the release of insulin into the blood stream. The cell surface amounts of GLUT2 are maintained constant via recycling of GLUT2. Adipocytes, the main cell type of adipose tissue, sense the increase in circulating insulin levels resulting in an induction of p‐AKT‐dependent signaling cascades that favor the fusion of GLUT4 storage vesicles with the plasma membrane, increasing the surface expression of GLUT4. When GLUT4 is translocated at the cell surface, glucose will enter into adipocytes and be stored as triglycerides within the lipid droplets. Concomitantly, insulin acts on the main liver cells, hepatocytes, by inducing a cascade of signaling events downstream of the insulin receptor. These signals will restructure the genomic program of the hepatocytes towards anabolic processes, either storing glucose that enters the cells in a concentration‐dependent manner via GLUT2 into glycogen, or utilizing the glucose for glycolysis. In addition to controlling glucose levels, hepatocytes also participate in the regulation of cholesterol levels. To achieve this function, circulating low‐density lipoprotein cholesterol (LDL‐C) is taken up by the hepatocytes and sent to lysosomes, where the digested cholesterol will be extracted via the Niemann‐Pick proteins into the cytosol. Cytosolic cholesterol can then be used either for incorporation into membranes or for bile acid production. Examples of endocytic components that play a role in these metabolic processes are labeled in red. EE, early endosomes; ERC, endosomal recycling compartment; GSVs, GLUT4 storage vesicles; ISGs, insulin secretory vesicles; LYS, lysosome; TG, triglycerides; IR, insulin receptor; LDLR, LDL receptor; NPC, Niemann‐Pick protein
Figure 2
Figure 2
Involvement of endocytic components in systemic metabolism during the fasting period. During fasting, blood glucose levels drop, leading to a reduction in insulin secretion by pancreatic β‐cells. Instead glucagon is secreted from pancreatic α‐cells, which mainly acts on hepatocytes and induces a signaling cascade that shifts the genomic program towards catabolism, producing glucose either by the breakdown of glycogen or de novo synthesis from pyruvate through gluconeogenesis. Hepatocytes will also produce energy by breaking down their triglyceride stores into non‐esterified fatty acids and burning them via β‐oxidation. Concomitantly, in the adipocytes, the drop in insulin will stop GLUT4 translocation, which will be removed from the plasma membrane through endocytosis and stored in GLUT4 storage vesicles, leading to the arrest of glucose uptake by the adipocyte. This is also accompanied by an activation of triglyceride lipolysis releasing glycerol and NEFA into the blood. Glycerol will be used by hepatocytes to generate pyruvate essential for gluconeogenesis, and NEFA will be burned via β‐oxidation. Examples of endocytic components that play a role in these metabolic processes are labeled in red. EE, early endosomes; ERC, endosomal recycling compartment; GSVs, GLUT4 storage vesicles; ISGs, insulin secretory vesicles; LYS, lysosome; TG, triglycerides; GR, glucagon receptor; IR, insulin receptor; NEFA, non‐esterified fatty acids
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