Obesity is a disease that affects 33% of the US population, leads to the development of severe comorbidities such as diabetes, and results in overall poor quality of life. The development of obesity is influenced by many genetic, environmental, and cultural factors but ultimately is strongly dependent on caloric intake and diet. Gastrointestinal (GI) peptides and hormones are known to influence appetite, satiation, and energy expenditure through interactions with cognate receptors expressed in the brain or in peripheral nerve fibers making them an appealing therapeutic target for obesity treatment. Our laboratory has previously described a putative role for a particular GI peptide, peptide tyrosine-tyrosine (PYY), where application of PYY to the oral cavity in mice promotes decreased food intake and weight loss without causing conditioned taste aversion (Acosta et al 2012, Hurtado et al 2013). Notably, cognate neuropeptide Y receptors (YRs) for PYY have been detected in taste buds as well as receptors for leptin and GLP-1, two other pro satiety hormones (La Sala et al 2013, Shigamura et al 2004, Martin et al 2009). The discovery of satiety hormone receptors in taste buds is intriguing, specifically because of the influence of taste on both feeding behavior and caloric consumption. Based on preliminary RNA sequencing of the murine taste bud transcriptome conducted in our laboratory, we performed immunohistochemical (IHC) staining of murine circumvallate taste buds and discovered that key receptors for adiponectin (APN), Adipor1 and Cdh13, are expressed in PLC?+ taste receptor cells. This finding is significant because APN is a protein known to be down-regulated in obese humans and known to effect body weight and glucose homeostasis in mice (Arita et al 1999, Kubota et al 2002). In addition, APN is present in saliva as well as in the circulation although a specific role for salivary APN has yet to be identified. Using a behavioral brief-access taste response test in adiponectin null (APN-/-) mice, we have further discovered that these mice display an increased sensitivity to intralipid stimulus. Based on these results, we will first set to fully characterize the expression profile of Adipor1 and Cdh13 in murine circumvallate taste buds by performing dual IHC staining using antibodies for Adipor1 and Cdh13 as well as antibodies for established taste receptor cell markers. Next, we will assess the functional effects of salivary APN on intralipid taste sensing in a mouse model that expresses APN solely in saliva, using a brief-access taste response test. Finally we will use this same salivary adiponectin mouse model to study the effects of salivary APN on food intake and body weight gain when exposed to a high fat diet. The outcome of this project will provide insight into the role of salivary APN on taste perception and demonstrate the therapeutic potential of salivary APN modulation, as an effector of food intake and weight loss. Hypothesis: We hypothesize that salivary adiponectin modulates intralipid taste perception in mice.
Aim 1 : Characterize Adipor1, Adipor2, and Cdh13 receptor gene expression profiles in Type I, Type II, and Type III TRCs Aim 2: Determine the effect of salivary APN on intralipid taste response in APN-/- mice Aim 3: Determine the effect of salivary adiponectin on food intake and body weight in APN-/- mice
Better understanding of the role of salivary hormones and their interaction with taste receptor cells will provide important information on how the perception of taste influences feeding behavior and diet. This project seeks to characterize the role of salivary adiponectin on taste perception and food intake in mice in order to gain insight into new potential therapeutic targets for weight loss in obese patients.
| Crosson, Sean M; Dib, Peter; Smith, J Kennon et al. (2018) Helper-free Production of Laboratory Grade AAV and Purification by Iodixanol Density Gradient Centrifugation. Mol Ther Methods Clin Dev 10:1-7 |
