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Investigation of Free Fatty Acid on Concerted Trafficking of K ATP and Kv2.1 Channels in the Adipoinsular Axis in vivo and in vitro
Author(s) -
Ruan JingSyuan,
Chen PeiChun
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.780.15
Subject(s) - leptin , endocrinology , medicine , lipotoxicity , insulin , insulin resistance , hyperpolarization (physics) , chemistry , potassium channel , fatty acid , biology , biochemistry , obesity , organic chemistry , nuclear magnetic resonance spectroscopy
Type 2 diabetes is the most prevalent metabolic syndrome worldwide and obesity is the major risk factor. The high level of fatty acid accumulation can be observed in the pancreatic β‐cells so called lipotoxicity. The overload of free fatty acid contributes to pancreatic β‐cells apoptosis and dysfunction that are associated with the disease progression. Insulin and leptin form as the adipoinsular axis, a dual regulatory loop maintains nutrient balance. High blood glucose triggers insulin release in pancreatic β‐cells and insulin further stimulates leptin release from adipocytes. Leptin can directly act on pancreatic β‐cells to suppress insulin secretion. Plasma leptin concentration is proportional to body fat mass so it's not surprising that high plasma leptin can be observed in obese individuals. Unfortunately, leptin resistance is easily to develop therefore, chronic leptin treatment is not an effective way to treat obesity. ATP‐sensitive potassium channels (K ATP channels) are essential to the connection between membrane excitability and glucose‐stimulated insulin secretion (GSIS). Physiologic role of K ATP channels depend on the correct trafficking and cell surface expression. Based on the previous publication, leptin signaling leads to simultaneous increase surface expression of K ATP and Kv2.1 channels that is dependent on AMPK, PKA as well as actin depolymerization and this action would cause membrane potential hyperpolarization to reduce insulin secretion. The goal of this study is to understand the effect of fatty acid on trafficking of K ATP and Kv2.1 channels in adipoinsular axis. We hypothesize that free fatty acid would induce the change of membrane potentials that results in the defect of K ATP and Kv2.1 channels trafficking and this would cause cell malfunction and lead to cell death in obesity‐induced type 2 diabetic β ‐cells. The following three specific aims are proposed to comprehensively investigate the above hypothesis: Aim 1: to evaluate the effect of free fatty acid on the adipoinsular axis in vivo using molecular genetic approaches as well as electrophysiological experiments. Aim 2: to understand if concerted trafficking of K ATP and Kv2.1 channels plays a role in free fatty acid induced apoptosis using pharmacological approaches. Aim 3: to manipulate whether concerted trafficking of K ATP and Kv2.1 channels can recover the adipoinsular axis and enhance cell viability using type 2 diabetes animal model, including diet induced obese mice and leptin receptor knockout mice ( db/db ). The study provides the new insight by manipulating K ATP and Kv2.1 channels trafficking to overcome metabolic diseases related to unbalanced adipoinsular axis. Support or Funding Information This work are supported by MoST grants (103‐2320‐B‐006‐005‐MY2 and 105‐2628‐B‐006‐MY3) to P‐C Chen.