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Sci. STKE, 1 August 2006
Vol. 2006, Issue 346, p. re7
[DOI: 10.1126/stke.3462006re7]


Role of Insulin, Adipocyte Hormones, and Nutrient-Sensing Pathways in Regulating Fuel Metabolism and Energy Homeostasis: A Nutritional Perspective of Diabetes, Obesity, and Cancer

Stephen Marshall*

Hexos Inc., 18304 NE 153rd Street, Woodinville, WA 98072, USA.

Gloss: The classical view of the endocrine system and how it controls intermediary metabolism is rapidly changing with the realization that metabolic fuels can function outside of their traditional role as substrates for the generation of high-energy molecules and as precursors for the biosynthesis of macromolecules. Specifically, both glucose and amino acids are now recognized as important signaling molecules in nutrient-sensing transductional pathways, collectively known as nutrient signaling pathways. Three distinct nutrient signaling pathways have been identified and appear to play a major role in human health and disease. The hexosamine signaling pathway senses changes in intracellular glucose availability and attempts to restore fuel and energy homeostasis by regulating glucose metabolism, lipid metabolism, and the release of adipocyte-specific hormones. Under hyperglycemic conditions, enhanced flux through the hexosamine signaling pathway leads to insulin resistance, which worsens control of blood glucose levels in diabetics and serves as a prominent risk factor in the development of type 2 diabetes. The mTOR (mammalian target of rapamycin) signaling pathway monitors intracellular amino acid levels and regulates protein synthesis, cell growth, and ribosomal biogenesis. Finally, the adenosine monophosphate–activated protein kinase (AMPK) signaling pathway senses intracellular energy levels and restores adenosine triphosphate (ATP) levels by inhibiting anabolic pathways that consume ATP and stimulating catabolic pathways that generate cellular energy. Genetic abnormalities in signaling components of the mTOR and AMPK pathways have recently been linked to unregulated cell growth and the development of various forms of cancer. We illustrate how nutrient signaling pathways are interconnected at multiple levels, tightly coupled to insulin signaling, and linked to the release of metabolic hormones from adipose tissue. Moreover, we propose that nutrient signaling pathways serve as components of a larger "metabolic regulatory network" that controls fuel and energy metabolism (at the cell, tissue, and whole-body levels) and links nutrient availability with cell growth and proliferation. This perspective provides a conceptual framework for understanding how nutrients and hormones interact in the control of intermediary metabolism, and how nutrient excess and molecular abnormalities in insulin signaling and nutrient signaling pathways can lead to the pathogenesis of various metabolic diseases and to carcinogenesis.

*Corresponding author. E-mail, hexos06{at}

Citation: S. Marshall, Role of Insulin, Adipocyte Hormones, and Nutrient-Sensing Pathways in Regulating Fuel Metabolism and Energy Homeostasis: A Nutritional Perspective of Diabetes, Obesity, and Cancer. Sci. STKE 2006, re7 (2006).

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