An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption.
Fat is delivered to tissues by apoB-containing lipoproteins synthesized in the liver and intestine with the help of an intracellular chaperone, microsomal triglyceride transfer protein (MTP). Leptin, a hormone secreted by adipose tissue, acts in the brain and on peripheral tissues to regulate fat storage and metabolism. Our aim was to identify the role of leptin signaling in MTP regulation and lipid absorption using several mouse models deficient in leptin receptor (LEPR) signaling and downstream effectors. Mice with spontaneous LEPR B mutations or targeted ablation of LEPR B in proopiomelanocortin (POMC) or agouti gene related peptide (AGRP) expressing cells had increased triglyceride in plasma, liver, and intestine. Furthermore, melanocortin 4 receptor (MC4R) knockout mice expressed a similar triglyceride phenotype, suggesting that leptin might regulate intestinal MTP expression through the melanocortin pathway. Mechanistic studies revealed that the accumulation of triglyceride in the intestine might be secondary to decreased expression of MTP and lipid absorption in these mice. Surgical and chemical blockade of vagal efferent outflow to the intestine in wild-type mice failed to alter the triglyceride phenotype, demonstrating that central neural control mechanisms were likely not involved in the observed regulation of intestinal MTP. Instead, we found that enterocytes express LEPR, POMC, AGRP, and MC4R. We propose that a peripheral, local gut signaling mechanism involving LEPR B and MC4R regulates intestinal MTP and controls intestinal lipid absorption.
Iqbal
Jahangir
J
Department of Cell Biology and Pediatrics, State University of New York Health Science Center at Brooklyn (SUNY Downstate Medical Center), Brooklyn, NY, USA.
Li
Xiaosong
X
Chang
Benny Hung-Junn
BH
Chan
Lawrence
L
Schwartz
Gary J
GJ
Chua
Streamson C
SC
Hussain
M Mahmood
MM
D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000294:innervation; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000294:innervation / Q000378:metabolism; D053486:Melanocortins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism; D014628:Vagotomy
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D002352:Carrier Proteins; D004041:Dietary Fats; D020738:Leptin; D053486:Melanocortins; D044105:Receptor, Melanocortin, Type 4; D054411:Receptors, Leptin; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D011333:Pro-Opiomelanocortin; D002784:Cholesterol