Leptin is a peptide hormone produced by adipose tissue and released in proportion to adipose mass. Leptin acts on the central nervous system to increase lipolysis and heat production through activation of the sympathetic nervous system. It is also a potent inhibitor of feeding behavior. A great deal is known about how leptin can invoke changes in transcription, resulting in the enhancement or suppression of the synthesis of peptide neurotransmitters that regulate feeding or metabolism. However, the mechanism by which leptin generates rapid changes in the excitability of neural pathways regulating autonomic and behavioral functions is less certain. A confounding factor in understanding rapid leptin signaling may be the high degree of cooperativity that exists between leptin transduction mechanisms and those of other agonists. This relationship may cause leptin action to be """"""""gated"""""""" by parallel signals or, vice versa, leptin may """"""""gate"""""""" the effectiveness of other agonists involved in autonomic or behavioral control. A synergistic relationship between leptin and other factors operating simultaneously may offer an intriguing explanation for the effects of temperature on the effectiveness of leptin and the effect of leptin to sensitize thermoregulatory mechanisms. The dorsal vagal complex [DVC] has receptor elements for leptin and receives thyrotropin releasing hormone [TRH]-ergic input from pathways known to command sympathetically-mediated increases in heat production. We propose that leptin and TRH action on DVC neurons is highly cooperative to the point that the presence of one agonist essentially """"""""gates"""""""" the action of the other. Our preliminary results show that leptin applied alone to the dorsal medulla has no consistent effects on brown adipose tissue [BAT] temperature. TRH produces a small increase in BAT temperature. However, TRH and leptin applied to the dorsal medulla together produce an increase in BAT and core temperature 300 percent greater than leptin or TRH alone. This effect can be elicited in the acute decerebrate rat, suggesting that the effect is mediated entirely by the brainstem. Obesity is the consequence of a failure to balance feeding behavior with metabolic activity and has reached epidemic levels of incidence in virtually every modern society. Obesity exacerbates, or is a frank causative factor, in a number of chronic diseases. The accumulated financial burden associated with the effect of obesity to worsen the health of the population is over $240 billion per year. Unfortunately, evidence suggests that the incidence of obesity will increase over time. Clearly, a better understanding of the control of energy expenditure should be crucial to the control of obesity and is of critical scientific, clinical and societal importance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055866-04
Application #
7993594
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
He, Janet
Project Start
2007-12-15
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$315,131
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
Viard, Edouard; Rogers, Richard C; Hermann, Gerlinda E (2012) Systemic cholecystokinin amplifies vago-vagal reflex responses recorded in vagal motor neurones. J Physiol 590:631-46
McDougal, David H; Hermann, Gerlinda E; Rogers, Richard C (2011) Vagal afferent stimulation activates astrocytes in the nucleus of the solitary tract via AMPA receptors: evidence of an atypical neural-glial interaction in the brainstem. J Neurosci 31:14037-45
Rogers, Richard C; McDougal, David H; Hermann, Gerlinda E (2011) Leptin amplifies the action of thyrotropin-releasing hormone in the solitary nucleus: an in vitro calcium imaging study. Brain Res 1385:47-55
Barnes, Maria J; Rogers, Richard C; Van Meter, Montina J et al. (2010) Co-localization of TRHR1 and LepRb receptors on neurons in the hindbrain of the rat. Brain Res 1355:70-85
Rogers, Richard C; Barnes, Maria J; Hermann, Gerlinda E (2009) Leptin ""gates"" thermogenic action of thyrotropin-releasing hormone in the hindbrain. Brain Res 1295:135-41