Obesity is a national and global epidemic and limiting energy intake would be an effective treatment. Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are each satiating signals secreted from the small intestine in response to dietary lipids, and the combination of apo AIV plus CCK has a synergistic effect on the suppression of food intake. However, where and how apo AIV and CCK interact to inhibit food intake remain unclear. CCK acts on local receptors on vagal afferent nerves and sends a satiating message to the hindbrain. Recently, we found that peripheral apo AIV requires an intact CCK system to relay satiating signals to the hindbrain. In addition, subdiaphragmatic selective vagal deafferentation (SDA) attenuates the inhibition of food intake as well as neuronal activation in the hindbrain induced by intraperitoneal (ip) apo AIV. We also found that apo AIV increases CCK secretion in vitro and in vivo. These findings suggest that the interaction of CCK and apo AIV in the control of food intake might be mediated via a co-dependent secretion and/or a combined activation of vagal afferent nerves. Our central hypothesis is that apo AIV increases CCK secretion in response to lipids, and that apo AIV also enhances CCK's action. The first specific aim will test the hypothesis that apo AIV dose-dependently increases the amount of CCK secreted in response to dietary lipids. This will include determining the involvement of apo AIV in stimulating G-protein signaling cascades and cyclic AMP-protein kinase A (cAMP-PKA) pathways important for CCK secretion.
In Specific Aim 2, we will test the hypothesis that peripheral apo AIV increases vagal afferent nerve activity, either by acting directly on the neurons or else by potentiating CCK's action on them. Successful completion of this grant application will identify the physiological and cellular mechanisms by which CCK and apo AIV interact in the periphery to increase activation of vagal afferent neurons and contribute to limiting meal size. This will provide a novel concept for generating pharmacological approaches to influence food intake and body weight.

Public Health Relevance

The objective of this project is to elucidate the mechanisms through which apo AIV dose-dependently stimulates CCK secretion in response to dietary lipids, and how apo AIV potentiates CCK's action on the afferent vagus, leading to decreased food intake. Given the growing incidence of obesity, identifying the mechanism of satiation factors such as CCK and apo AIV is expected to have a significant public health impact.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Digestive Diseases and Nutrition C Subcommittee (DDK)
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Podskalny, Judith M,
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University of Cincinnati
Schools of Medicine
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Zhan, Jesse; Weng, Jonathan; Hunt, Brian G et al. (2018) Apolipoprotein A-IV enhances cholecystokinnin secretion. Physiol Behav 188:11-17
King, Alexandra; Yang, Qing; Huesman, Sarah et al. (2015) Lipid transport in cholecystokinin knockout mice. Physiol Behav 151:198-206
Wang, Fei; Kohan, Alison B; Lo, Chun-Min et al. (2015) Apolipoprotein A-IV: a protein intimately involved in metabolism. J Lipid Res 56:1403-18
Kohan, Alison B; Wang, Fei; Lo, Chun-Min et al. (2015) ApoA-IV: current and emerging roles in intestinal lipid metabolism, glucose homeostasis, and satiety. Am J Physiol Gastrointest Liver Physiol 308:G472-81
Lo, Chunmin C; Davidson, W Sean; Hibbard, Stephanie K et al. (2014) Intraperitoneal CCK and fourth-intraventricular Apo AIV require both peripheral and NTS CCK1R to reduce food intake in male rats. Endocrinology 155:1700-7