Table of Contents

    Organ Crosstalk in Obesity and NAFLD

    The liver is vital to various metabolic functions including lipid and glucose metabolism. In order to maintain homeostasis, efficient gut-liver and adipose tissue-liver communications are needed1,2. Research indicates that obesity induced dysfunctions within these crosstalks can lead to imbalances in energy metabolism and contribute to the pathogenesis of metabolic diseases such as nonalcoholic fatty liver disease (NAFLD)1,3. As the global prevalence of NAFLD continues to rise, researchers are working towards understanding the mechanisms behind organ crosstalk in obesity and NAFLD1,4,5.

    Overview of the Liver

    A properly functioning liver is vital to maintaining homeostasis because it performs numerous functions needed for energy metabolism5,6,7,8. The liver continually sends and receives nutrients and signals from the gastrointestinal (GI) tract and adipose tissue in order to perform its metabolic functions6.

    Energy Metabolism in the Liver

    The liver contributes to energy metabolism by maintaining a balance between glucose and lipid levels. This balance depends on being in a fed or fasted state5,7 as depicted in the diagram below:

    A diagram depicting how the liver maintains balance between glucose and lipid levels.

    Organ Crosstalk in Liver Energy Metabolism

    Evidence demonstrates that glucose and lipid metabolism are regulated by crosstalk between the liver and gastrointestinal tract, as well as the liver and adipose tissue (AT)2,5.

    A diagram illustrating how glucose and lipid metabolism are regulated by crosstalk between the liver and GI tract.

    The Gut-Liver Axis

    The gut-liver axis (GLA) refers to the physical and biological connections between the liver and organs in the GI tract: stomach, intestines, and pancreas. The GLA also includes the gut microbiota (GM) and intestinal barrier1,9.

    Gut-Liver Crosstalk in Energy Metabolism

    The crosstalk between GLA components helps regulate glucose and lipid metabolism1,5,9,10. Hormones, proteins, and metabolites are examples of signaling molecules produced by the GLA to regulate these communications which, in turn, control glucose and lipid metabolism in the liver1,5,11,12,13,14.

    Gut-Liver Crosstalk and De Novo Lipogenesis

    Within the GLA, the pancreas produces insulin and glucagon, two hormones needed to regulate liver de novo lipogenesis (DNL). Research shows that both glucose concentration and insulin signaling promote DNL through the activation of transcription factors4,15. Increased lipid and glucagon levels then inhibit DNL to maintain liver lipid homeostasis4,15.

    Adipose Tissue-Liver Axis

    The adipose tissue-liver axis refers to connections between body fat and the liver. There are three types of adipose tissue found throughout the body16,17. The most common type of AT is white adipose tissue (WAT) which frequently interacts with the liver to promote energy homeostasis18,19.

    Adipose Tissue-Liver Crosstalk in Energy Metabolism

    Adipose tissue and the liver produce signaling molecules such as hormones to communicate current energy status and metabolic needs5. Hormones exclusively produced by adipose tissue are commonly referred to as adipokines20. Adiponectin and leptin are two key adipokines needed to maintain the crosstalk between adipose tissue and the liver to support glucose and lipid metabolism5,20.

    Adipose Tissue-Liver Crosstalk and Adipokines

    In the liver, adiponectin and leptin trigger the AMP protein kinase (AMPK) and proliferator-activated receptor (PPARα) signaling mandatory for regulating adipose tissue-liver crosstalk which then controls both glucose and lipid metabolism2,5,20.

    Obesity Driven Imbalances in Organ Crosstalk

    Research demonstrates that obesity is a key contributor to the dysregulation of both gut-liver crosstalk and adipose tissue-liver crosstalk1,15. The resulting imbalances in both glucose and lipid metabolism can lead to metabolic diseases such as non-alcoholic fatty liver disease (NAFLD)4,5,7.

    A diagram illustrating the obesity driven imbalances in organ crosstalk and energy metabolism.

    Obesity Induced Dysfunction in Gut-Liver Crosstalk

    Studies indicate that obesity can cause interruptions in gut-liver crosstalk by altering the gut microbiota1,9.

    Obesity induced GM alterations can lead to:

    • Liver inflammation1,9,21
    • Insulin resistance1,9,21
    • Increased liver DNL1,9,21

    Obesity Induced Dysfunction in Adipose Tissue-Liver Crosstalk

    Evidence demonstrates that obese adipose tissue alters the adipokine and cytokine secretion patterns of adipose tissue20,22.

    These changes in AT secretion can lead to:

    • Insulin resistance 23,24
    • Promotion of liver DNL15
    • Lack of control over liver gluconeogenesis15

    Organ Crosstalk in Obesity and NAFLD

    Insulin resistance and the dysregulation of energy metabolism in the liver caused by obesity induced changes to organ crosstalk can lead to the development of metabolic diseases such as NAFLD3,4,14,25. Many researchers propose that excessive lipid accumulation caused by imbalances in gut-liver and adipose tissue-liver crosstalk can initiate a cycle of damaging liver inflammation  and lead to NAFLD1,2,3,9,20,21,26.

    This diagram outlines the altered organ crosstalk and projected progression from obesity to NAFLD.

    Efficient crosstalk between the liver, GI tract, and adipose tissue is necessary to regulate lipid and glucose metabolism in the liver1,2. Many signaling molecules help  maintain the communication pathways that support the liver’s crosstalk with the GI tract and adipose tissue1,2. Research demonstrates that obesity can induce many changes to liver-organ crosstalk including alterations to the gut microbiota and adipose tissue adipokine secretion patterns1,9,20,21,22. Increases in lipid and glucose production within the liver can contribute to the pathogenesis of metabolic diseases such as NAFLD4,15,25,27. However, more research is still needed in order to fully elucidate the relationship between organ crosstalk in obesity and NAFLD.

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