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Vol. 52, Issue 1, 35-62, March 2000
Second Department of Internal Medicine, Kobe University
School of Medicine, Kobe, Japan
I. Introduction
II. Leptin and Body Weight Regulation
III. Neuropeptidergic Cascade Downstream of Leptin Signaling
IV. Key Components in Body Weight Regulation and Implications of
Transgenic Animal Models
A. Hypothalamic Stimulators of Food Intake
1. NPY.
2. MCH.
3. Orexin.
4. Galanin.
5. Opioid Peptides.
6. AGRP.
7. Other Orexigenic Signals.
B. Hypothalamic Inhibitors of Food Intake
1. MC.
2. CRF and Urocortin.
3. GLP-1.
4. Bombesin.
5. CCK.
6. Serotonin.
7. Cytokine.
8. Other Anorexigenic Signals.
C. Regulators of Thermogenesis: Sympathetic Nervous System
(SNS)-UCP Axis
D. Other Regulators
V. Advanced Gene Targeting
VI. Conclusions
Acknowledgments
References
Energy homeostasis is accomplished through a highly integrated and redundant neurohumoral system. Recently, novel molecular mediators and regulatory pathways for feeding and body weight regulation have been identified in the brain and the periphery. Because of the multitude and complexity of disturbances in energy intake, expenditure, and partitioning that are associated with obesity, it has been difficult to determine which abnormalities are causative versus less important phenomena that are consequences of the altered neuroendocrine and metabolic milieu. Transgenic technology has provided new opportunities to modify the complex body weight-regulating system and to assess the relative importance of the individual components. Observations of mutant mice have shed new light on the understanding of energy homeostasis equation. Once created, transgenic animal models may be useful in assessing the efficacy or determining the mode of action of potential new therapeutic agents. However, the interpretation of targeted mutation is sometimes not straightforward in unraveling the physiology because of the redundancy and compensation of the regulatory machinery, as well as the inherent problems of manipulation of the gene. Modifying the synthesis of a particular gene at all sites and developmental stages may be a relatively crude way of investigating its functions. Advanced gene-targeting strategies aimed at specific alterations (on and off) of a gene product at desired tissues and times could lead to a better understanding of the system.
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