Central proopiomelanocortin (POMC) neuron, a circuit that promotes anorectic feeding behavior and negative energy balance, is one of the best-defined neural networks regulating metabolic function. Nevertheless, the extent to which POMC neurons integrate these metabolic signals throughout the CNS remains unclear. POMC neurons reside in the mediobasal hypothalamus, but a distinct lack of cytological organization has made them relatively intractable to anatomical analysis. Likewise, it is well-established that changes in the feeding state of an organism can rewire hypothalamic circuits, but the effects of diet on POMC neural plasticity has not been directly examined. To complete the anatomical map of central POMC integration and examine the effects of diet-induced rewiring of hypothalamic circuits, we will utilize transgenic animal models, trans-synaptic viral tracing, and single cell electrophysiology techniques. In the first set of experiments, replication-deficient Cr-expressing canine adenovirus (CAV-Cre) vectors will be used to functionally re- activate neural-specific Pomc deficient mice with a LoxP-flanked neo cassette in the neural enhancer module of Pomc. Because CAV-Cre specifically infects receptors at the synaptic terminal, the number of re-activated POMC neurons will be dependent on the abundance of POMC innervations at a distal target site. To directly examine POMC morphology and physiology at the cellular level, we will use single cell patch clamp techniques to measure basal neural activity and simultaneously label cells with neurobiotin. These experiments will be followed by different diet paradigms, which will allow us to examine the effects of acute versus chronic changes in feeding on the morphology and synaptic activity of POMC neurons. Finally, we will synthesize the effects of diet on the POMC network by applying our feeding paradigms to transgenic Pomc-Cre mice expressing Cre- dependent fluorescent dendritic and axonal markers. These mice will allow us to study circuit-level changes in POMC innervations, and will allow us to reconstruct the central POMC network into a complete atlas. Taken together, deciphering the structure and function of central POMC neurons will lend insight into neural control of energy homeostasis, critical for combating the worldwide obesity epidemic.
Obesity and related metabolic complications constitute over $150 billion in healthcare spending annually;therefore it is imperative for both the health and economy of the United States to develop therapeutics to combat this epidemic. Central proopiomelanocortin neurons are well known for their role in anorectic feeding behavior and energy expenditure, but the anatomy and plasticity of this circuit remains unclear. To facilitate an understanding of how the nervous system regulates metabolism and expedite the development of obesity-related therapeutics, the objective of this proposal is to elucidate the ful anatomical map of the proopiomelanocortin network and to determine how changes in diet can affect proopiomelanocortin physiology.
|Lam, Daniel D; Attard, Courtney A; Mercer, Aaron J et al. (2015) Conditional expression of Pomc in the Lepr-positive subpopulation of POMC neurons is sufficient for normal energy homeostasis and metabolism. Endocrinology 156:1292-302|
|Lam, Daniel D; de Souza, Flavio S J; Nasif, Sofia et al. (2015) Partially redundant enhancers cooperatively maintain Mammalian pomc expression above a critical functional threshold. PLoS Genet 11:e1004935|
|Mercer, Aaron J; Stuart, Ronald C; Attard, Courtney A et al. (2014) Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice. Am J Physiol Endocrinol Metab 306:E904-15|
|Mercer, Aaron J; Hentges, Shane T; Meshul, Charles K et al. (2013) Unraveling the central proopiomelanocortin neural circuits. Front Neurosci 7:19|