Abstract
The hormone leptin regulates fat storage and metabolism by signaling through the brain and peripheral tissues. Lipids delivered to peripheral tissues originate mostly from the intestine and liver via synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins. An intracellular chaperone, microsomal triglyceride transfer protein (MTP), is required for the biosynthesis of these lipoproteins, and its regulation determines fat mobilization to different tissues. Using cell culture and animal models, here we sought to identify the effects of leptin on MTP expression in the intestine and liver. Leptin decreased MTP expression in differentiated intestinal Caco-2 cells, but increased expression in hepatic Huh7 cells. Similarly, acute and chronic leptin treatment of chow diet-fed WT mice decreased MTP expression in the intestine, increased it in the liver, and lowered plasma triglyceride levels. These leptin effects required the presence of leptin receptors (LEPRs). Further experiments also suggested that leptin interacted with long-form LEPR (ObRb), highly expressed in the intestine, to down-regulate MTP. In contrast, in the liver, leptin interacted with short-form LEPR (ObRa) to increase MTP expression. Mechanistic experiments disclosed that leptin activates signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling pathways in intestinal and hepatic cells, respectively, and thereby regulates divergent MTP expression. Our results also indicated that leptin-mediated MTP regulation in the intestine affects plasma lipid levels. In summary, our findings suggest that leptin regulates MTP expression differentially by engaging with different LEPR types and activating distinct signaling pathways in intestinal and hepatic cells.
Highlights
The hormone leptin regulates fat storage and metabolism by signaling through the brain and peripheral tissues
We show that leptin signals through signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways in the intestinal and liver cells, respectively, after binding to different types of leptin receptors (LEPRs) expressed in these cells to regulate differential microsomal triglyceride transfer protein (MTP) expression in these tissues
Leptin down-regulates MTP expression and apolipoprotein B (apoB) secretion; whereas in the liver cells, leptin up-regulates MTP expression and apoB secretion (Fig. 1). These effects require the presence of LEPR in these tissues, as ablation of LEPR in the intestine increases intestinal MTP expression and plasma triglyceride; and hepatic ablation of LEPR decreases hepatic MTP expression (Fig. 6)
Summary
The hormone leptin regulates fat storage and metabolism by signaling through the brain and peripheral tissues. Acute and chronic leptin treatment of chow diet-fed WT mice decreased MTP expression in the intestine, increased it in the liver, and lowered plasma triglyceride levels These leptin effects required the presence of leptin receptors (LEPRs). The long-form (ObRb), highly expressed in the intestine, has a 302-amino acid long cytoplasmic domain containing both JAK2 and signal transducer and activator of transcription (STAT)-binding sites. ObRa, which is ubiquitously expressed, lacks the cytoplasmic domain necessary for STAT signaling [29] This receptor contains the conserved box 1 motif present in cytokine receptors [38], which is required for the association of JAK2 with cytokine receptor proteins [39] and has been shown to perform leptin signaling [35, 40, 41]. ObRa signals through extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) pathways by direct phosphorylation of growth factor receptor-bound protein 2 or insulin receptor substrate 1 by JAK2, respectively [42, 43]
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