This review highlights recent advances in the hormonal control of hypothalamic AMPK activity and the impact on appetite and energy metabolism. AMPK is an intracellular energy sensor that switches off ATP-consuming pathways and switches on ATP-producing pathways such as glucose uptake and fatty acid oxidation. In this regard, it is well positioned to respond to dynamic changes in metabolic state and nutritional over- or under-supply. Within the hypothalamus, AMPK responds to peripheral hormones that convey metabolic information based on increased plasma concentrations. For example, negative energy balance increases plasma ghrelin concentrations, increases hypothalamic AMPK and drives food intake. Conversely, plasma leptin concentrations are secreted in proportion to adipose levels and leptin suppresses hypothalamic AMPK activity and restricts food intake. This review explains that hypothalamic AMPK mediates neuroendocrine feedback control of energy metabolism. A current working model suggests that endocrine feedback influences hypothalamic AMPK via a number of mechanisms designed to shift an organism from negative to neutral energy balance. These mechanisms include (1) ghrelin stimulation of AMPK in NPY/AgRP in the arcuate nucleus (2) ghrelin stimulation of AMPK in the ventromedial hypothalamic nucleus, (3) a novel ghrelin-stimulated AMPK-dependent presynaptic mechanism that sustains AgRP neuron firing via a local synaptic memory system, (4) adiponectin stimulation of hypothalamic AMPK and (5) hypothalamic AMPK control of energy expenditure by thyroid hormone or leptin. The number of diverse mechanisms ensures hypothalamic AMPK drives the shift from negative to neutral energy balance and underscores the fundamental importance of hypothalamic AMPK to maintain neutral energy balance.
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