Seminar

Mitochondrial fusion proteins in hypothalamic POMC neurons regulate whole-body energy homeostasis

Marc Claret, PhD

In recent years, the mediobasal hypothalamus has been firmly established as a key area of the central nervous system implicated in the regulation of whole-body energy homeostasis. This is achieved through a complex sensing of hormones and nutrient-related signals, followed by its integration and coordination of precise neurochemical and neurophysiological responses. These effector mechanisms are critically mediated by specific populations of neurons of the arcuate nucleus of the hypothalamus. In particular, neurons expressing anorexigenic pro-opiomelanocortin (POMC) precursor have been extensively implicated in the regulation of appetite, body weight and metabolism. The precise molecular mechanisms by which POMC neurons are able to sense energy/nutritional cues are incompletely understood, although a number of sensing molecules (AMPK, SIRT1, mTOR) have been reported to play relevant roles in energy balance control. Interestingly, the activity of these proteins may be modulated by metabolic mitochondrial intermediates, and therefore the mitochondria can be viewed as an energy-sensing organelle. Mitochondrial dynamics is a process regulated by nutrient availability, so fusion and fission events may represent primary nutrient/energy sensing processes implicated in the hypothalamic regulation of energy balance. Using a combination of conditional mouse genetics, detailed physiology, electron microscopy and molecular biology our current studies reveal a novel role for mitochondrial fusion proteins in the hypothalamus in the control of body weight and glucose metabolism.