Gastroenterology

Gastroenterology

Volume 132, Issue 6, May 2007, Pages 2158-2168
Gastroenterology

The Role of CNS Fuel Sensing in Energy and Glucose Regulation

https://doi.org/10.1053/j.gastro.2007.03.049Get rights and content

Individual cells must carefully regulate their energy flux to ensure nutrient levels are adequate to maintain normal cellular activity. The same principle holds in multicellular organisms. Thus, for mammals to perform necessary physiological functions, sufficient nutrients need to be available. It is more complex, however, to understand how the energy status of different cells impacts on the overall energy balance of the entire organism. We propose that the central nervous system is the critical organ for the coordination of intracellular metabolic processes that are essential to guarantee energy homeostasis at the organismal level. In particular, we suggest that in specific hypothalamic neurons, evolutionarily conserved fuel sensors, such as adenosine monophosphate-activated protein kinase and mammalian target of rapamycin (mTOR), integrate sensory input from nutrients, including those derived from recently ingested food or those that are stored in adipose tissue, to regulate effector pathways responsible for fuel intake and utilization. The corollary to this hypothesis is that dysregulation of these fuel-sensing mechanisms in the brain may contribute to metabolic dysregulation underlying diseases, such as obesity and type 2 diabetes.

Section snippets

CNS Energy Balance Regulation: Integrating Lipostatic and Glucostatic Theories

Since the end of the 19th century, several efforts have been made to determine the CNS’ role in the regulation of energy metabolism. In the 1950s, Gordon Kennedy proposed that energy homeostasis is maintained through regulation of body fat, as a result of feedback signals arising from the fat depots that are sensed by the brain.13 The hormones leptin and insulin, respectively synthesized in adipose tissue and pancreas, circulate in proportion to body fat.14 Hence, they inform the CNS that

CNS Fuel-Sensing Mechanisms: AMPK and mTOR

Studies have demonstrated over the last 50 years that the glucostatic and lipostatic theories both have important limitations and caveats.32, 64, 65 The result has been a need for new conceptualizations concerning the neuronal mechanisms that regulate food intake and energy homeostasis. In the following section, we would like to propose that signals derived from both stored and immediately available fuels converge in the same intracellular signaling cascades in the CNS, where they are monitored

mTOR

In 1991, the target for the immunosuppressant macrolide rapamycin was identified and termed Target Of Rapamycin or TOR. The mammalian isoform (called mTOR and also known as FRAP, RAFT, RAPT, or SEP) is a ∼ 280-KDa protein, member of the phosphatidylinositol kinase–related protein kinase family.87 mTOR is a highly conserved serine-threonine kinase, and its activity controls critical aspects of cell growth regulation, including transcription, translation initiation and elongation, and cell-cycle

The Role of CNS Fuel-Sensing Pathways in Causing and Treating Obesity

Understanding the basic mechanisms by which caloric intake is matched to caloric expenditure does not necessarily result in new therapies for obesity. While the prevailing data make an excellent case that CNS fuel-sensing pathways are an important part of how energy balance is regulated, several issues make them difficult to target for the treatment of obesity. First, these fuel-sensing pathways are critical components of regulating cellular function. As a result, their role in peripheral cells

Conclusions

The brain is a critical organ for coordinating complex metabolic processes across various tissues that ensure the right nutrients reach the tissues at the time they need them. To do so, metabolic pathways in the CNS must be able to supervise fuel availability in both a direct and an indirect manner. Part of the direct monitoring of fuels involves neurons using highly conserved intracellular fuel-sensing pathways able to provide readout of cellular fuel availability to guide the organism in

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