Chronic fat ingestion results in diet-induced obesity. Information about the mechanism of diet-induced obesity and the dysregulation, if any, induced in different pathways would facilitate appropriate therapeutic targeting. Apo A-IV is emerging as a factor that could regulate intestinal responses to ingested lipids as well as satiety induction.  (Dys) regulation of apo A-IV synthesis in response to chronic lipid ingestion has been described and hence it is a molecule that could be manipulated to advantage.

Apo A-IV, described in the 1970s,  is a protein secreted by enterocytes along with chylomicrons and VLDL both of which are triglyceride rich lipoproteins. Biochemistry. 1977 Jan 25;16(2):271-8.    Human Apo A-IV synthesis is restricted to the small intestinal epithelial cells with higher synthesis in the jejunum than the ileum.  Synthesis is stimulated by active lipid absorption Am J Physiol. 1987 May;252(5 Pt 1):G662-6.  namely formation and secretion of chylomicrons. J Lipid Res. 1990 Sep;31(9):1613-25.   Triglycerides, Phospholipids, cholesterol and cholesteryl esters are packaged with apolipoproteins to form chylomicrons. While Apo A, B and C apoproteins are associated with chylomicrons, only apo A-IV synthesis and secretion seems to be stimulated by fat absorption. J Lipid Res. 1990 Sep;31(9):1613-25.  An intact enterohepatic circulation is necessary for the normal basal lymphatic output of apo A-IV as demonstrated by a reduction in apo A-IV synthesis by biliary diversion. J Lipid Res. 1986 Jan;27(1):30-9.   A gastric lipid load under normal conditions stimulates apo A-IV lymphatic output with increased plasma levels within 15  minutes and lasting for longer than 30 minutes. Am J Physiol. 1997 Apr;272(4 Pt 2):R1170-7.

Apo A-IV and Lipid ingestion

Lipid delivery into the ileum has been shown to result in inhibition of gastric emptying, intestinal motility, as well as pancreatic secretions- processes termed collectively as the ileal brake. While Peptide YY has been thought to mediate this ileal brake effect to a significant degree, it may not be the sole factor involved  Gut. 1987 Feb;28(2):166-70.   Lipids infused distally in the intestine ( ileum) can increase both proximal and distal intestinal apo A-IV synthesis and secretion. Apo A-IV has been demonstrated to inhibit gastric motility Am J Physiol. 1996 Jan;270(1 Pt 1):G49-53.    as well as gastric acid secretion. Gastroenterology. 1995 Nov;109(5):1583-8.     It remains a possibility that lipid-induced  Apo A-IV stimulation might play a role in mediating the ileal brake effects. At the same time, intravenous infusion of  Peptide YY has been shown to increase apo A-IV synthesis and lymphatic transport. Am J Physiol. 1999 Nov;277(5 Pt 1):G1081-7    and hence the effects of Peptide YY could be  mediated at least partially through apo A-IV.

Apo A-IV and satiety

Purified apo A-IV infusion intravenously into fasted rats significantly suppressed food consumption. Am J Physiol. 1992 Jun;262(6 Pt 1):G1002-6.   Apo A-IV protein as well as its mRNA  is present in the hypothalamus,   Am J Physiol Regul Integr Comp Physiol. 2001 May;280(5):R1382-7.  predominantly in the arcuate nucleus. Central administration of apo A-IV into the third ventricle decreased food intake in rats in a dose dependent manner and up to 50 times more potently than peripheral ( intravenous) administration.  J Clin Invest. 1993 Apr;91(4):1830-3.     Anti apo A-IV serum injected into rat third ventricle elicited a feeding response in fasted rats.   Am J Physiol Regul Integr Comp Physiol. 2001 May;280(5):R1382-7. Apo A-IV may thus act as a satiety factor following lipid ingestion. In the physiological context,  lipids produce significant apo A-IV  plasma levels within 15  minutes and lasting for longer than 30 minutes,  Am J Physiol. 1997 Apr;272(4 Pt 2):R1170-7.  which makes it likely that apo A-IV could indeed act as a physiological short term satiety factor. Apo A-IV levels show a diurnal rhythm corresponding with the nocturnal feeding in rodents   Am J Physiol. 1994 Nov;267(5 Pt 2):R1385-90.  further suggesting its physiological role in feeding regulation.

Chronic fat ingestion results in diet-induced obesity.  Consumption of a high fat diet initially increases Apo A-IV levels but over time this effect is attenuated Gastroenterology. 1990 Jan;98(1):17-24     with reduced apo A-IV mRNA and synthesis in the jejunal mucosa.  Am J Physiol Regul Integr Comp Physiol. 2001 Apr;280(4):R1155-61   

APO A-IV regulators

Apo A-IV in both the hypothalamus and intestine responds similarly to fasting and lipid ingestion.  Am J Physiol Regul Integr Comp Physiol. 2001 May;280(5):R1382-7.Fasting results in marked decrease in apo A-IV gene expression in the hypothalamus and intestines. While low fat feeds do not elicit any change in apo A-IV levels, lipid feeding increases both hypothalamic and intestinal apo A-IV levels. The ability of the various saturated and unsaturated fatty acids in triglycerides, to stimulate apo A-IV secretion remains to be clarified. CSF apo A-IV levels may regulate hypothalamic apo A-IV mRNA levels as suggested by studies using anti-apo A-IV antibodies.

Apo A-IV synthesis in the jejunum induced by jejunal lipid infusion is not affected by vagotomy suggesting a signal transduction independent of  the CNS. Am J Physiol. 1999 Nov;277(5 Pt 1):G1081-7.   But vagotomy did abolish the jejunal Apo A-IV synthesis induced by ileal lipid infusion. The Peptide YY mediated increase in apo A-IV synthesis mentioned above, might be mediated via the vagus, and hence vagotomy might prevent the fat induced Peptide YY effect on apo A-IV. A vagal unresponsiveness occurring with repeated fat ingestion could result in the decreased PYY efficacy in increasing apo -IV levels.

Neuropeptide Y (NPY) administration centrally into fasted rats increases hypothalamic apo A-IV mRNA,  Brain Res. 2003 May 9;971(2):232-8.    which could be a counter regulatory response to the orexigenic effect of neuropeptide Y. Interestingly, non-fasted rats fed with lipids which already have a high apo A-IV mRNA level in the hypothalamus did not show a further apo A-IV increase with NPY administration, probably due to a ceiling effect on mRNA increase or perhaps due to other mechanism related to lipid processing in the gut.

 Intravenous Leptin infusion attenuates the fat absorption-induced rise in Apo A-IV. Am J Physiol Regul Integr Comp Physiol. 2001 Sep;281(3):R753-9. suggesting a constant inhibitory influence by post-prandial Leptin on apo A-IV secretion and thus plasma chylomicron-triglyceride levels. The mechanism of action of Leptin in influencing Apo A-IV levels remains unclear although a direct effect on intestinal cells or an indirect effect on apo A-IV gene transcription remain a possibility. Induction of enzymes to facilitate beta oxidation of fatty acids might also  contribute to leptin's action. The initial increase in Apo A-IV levels with consumption of a high fat diet is attenuated over time Gastroenterology. 1990 Jan;98(1):17-24      and could well be secondary to the increase in leptin levels.

Insulin up-regulates the intestinal apo A-IV synthesis and secretion in humans and rodents. Diabet Med. 1997 Mar;14(3):242-7.     Insulin and leptin are hormones secreted in proportion to body fat mass and their regulation of apo A-IV levels suggest a role for apo A-IV in long term satiety control.

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