Dietary fat is an important mediator of atherosclerosis and obesity. Despite its importance in mediating metabolic disease, there is still much unknown about dietary fat absorption in the intestine and especially the detailed biological roles of intestinal apolipoproteins involved in that process. We were specifically interested in determining the physiological role of the intestinal apolipoprotein A-IV (A-IV) using A-IV knockout (KO) mice. A-IV is stimulated by fat absorption in the intestine and is secreted on nascent chylomicrons into intestinal lymph. We found that A-IV KO mice had reduced plasma triglyceride (TG) and cholesterol levels and that this hypolipidemia persisted on a high-fat diet. A-IV KO did not cause abnormal intestinal lipid absorption, food intake, or adiposity. Additionally, A-IV KO did not cause abnormal liver TG and cholesterol metabolism, as assessed by measuring hepatic lipid content, lipogenic and cholesterol synthetic gene expression, and in vivo VLDL secretion. Instead, A-IV KO resulted in the secretion of larger chylomicrons from the intestine into the lymph, and those chylomicrons were cleared from the plasma more slowly than wild-type chylomicrons. These data suggest that A-IV has a previously unknown role in mediating the metabolism of chylomicrons, and therefore may be important in regulating plasma lipid metabolism.

Adipose tissue distribution is an important determinant of obesity-related comorbidities. It is well established that central obesity (visceral adipose tissue accumulation) is a risk factor for many adverse health consequences such as dyslipidemia, insulin resistance and type-2-diabetes. We hypothesize that the metabolic dysregulation that occurs following high fat diet-induced increases in adiposity are due to alterations in visceral adipose tissue function which influence lipid flux to the liver via the portal vein. This metabolic pathology is not exclusively due to increases in visceral adipose tissue mass but also driven by intrinsic characteristics of this particular depot. In Experiment 1, high fat diet (HFD)-induced obese control (abdominal incision, but no fat manipulation) or autologous (excision and subsequent relocation of adipose tissue) subcutaneous tissue transplantation to the visceral cavity. In Experiment 2 mice received control surgery, subcutaneous fat removal or hetero-transplantation (tissue from obese donor) to the visceral cavity. Body composition analysis and glucose tolerance tests were performed 4 weeks post-surgery. Adipose mass and portal adipokines, cytokines, lipids and insulin were measured from samples collected at 5 weeks post-surgery. Auto- and hetero- transplantation in obese mice improved glucose tolerance, decreased systemic insulin concentration and reduced portal lipids and hepatic triglycerides compared with HFD controls. Hetero-transplantation of subcutaneous adipose tissue to the visceral cavity in obese mice restored hepatic insulin sensitivity and reduced insulin and leptin concentrations to chow control levels. Fat removal, however, as an independent procedure exacerbated obesity-induced increases in leptin and insulin concentrations. Overall subcutaneous adipose tissue protects against aspects of metabolic dysregulation in obese mice. Transplantation-induced improvements do not occur via enhanced storage of lipid in adipose tissue, however altered hepatic lipid regulation may play a contributory role.

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are gastrointestinal satiation signals that are stimulated by fat consumption. Previous studies have demonstrated that peripheral apo AIV cannot cross the blood-brain barrier. In the present study, we hypothesized that peripheral apo AIV uses a CCK-dependent system and intact vagal nerves to relay its satiation signal to the hindbrain. To test this hypothesis, CCK-knockout (CCK-KO) mice and Long-Evan rats that had undergone subdiaphragmatic vagal deafferentation (SDA) were used. Intraperitoneal administration of apo AIV at 100 or 200 μg/kg suppressed food intake of wild-type (WT) mice at 30, 60, and 90 min. In contrast, the same dose did not reduce food intake in the CCK-KO mice. Blockade of the CCK 1 receptor by lorglumide, a CCK 1 receptor antagonist, attenuated apo AIV-induced satiation. Apo AIV at 100 μg/kg reduced food intake in SHAM rats but not in SDA rats. Furthermore, apo AIV elicited an increase in c-Fos-positive cells in the nucleus of the solitary tract (NTS), area postrema, dorsal motor nucleus of the vagus, and adjacent areas of WT mice but elicited only an attenuated increase in these same regions in CCK-KO mice. Apo AIV-induced c-Fos positive cells in the NTS and area postrema of WT mice were reduced by lorglumide. Lastly, apo AIV increased c-Fos positive cells in the NTS of SHAM rats but not in SDA rats. These observations imply that peripheral apo AIV requires an intact CCK system and vagal afferents to activate neurons in the hindbrain to reduce food intake.

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