Hunger and satiety are a key feedback system. But the mechanistic basis for the regulation of food intake, energy expenditure, and glucose homeostasis remains unclear. Defining the neurons and pathways are associated with specific behaviors and physiologic responses could lead to novel therapeutic targets for medical and other interventions.
“The brain controls hunger and energy expenditure,” said Brad Lowell, MD, PhD, Professor of Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston. “The hypothalamus senses and uses feedback to regulate hunger. What we need is a wiring diagram that lets us understand and manipulate the functional neurocircuitry.”
Dr. Lowell discussed his work in understanding “The Wiring Diagram for Hunger” during the Saturday plenary session. The wiring diagram remains a work in progress.
The brain is a complex and often confusing space. There are multiple nuclei, or clusters of neurons, twisted and tangled together. Within each nucleus, neurons of similar, opposing, and unrelated function are intertwined.
Fortunately, many neurons express unique genetic markers. These markers allow the use of neuron-specific cre-expressing mice to identify individual neurons associated with specific states or activities and trace the neural circuits.
Cre-expressing mice allow researchers to track a variety of neuropeptides by identifying individual neurons that express POMC, AgRP, MCH, oxytocin and other receptors, transcription factors, and neurotransmitters. The technique uses neuron-specific knockout mice and a variety of tools to map and manipulate signaling and other activity. Activity can be tracked visually, using opto-genetics that allows for light-based control and reporting of neuronal activity or chemo-genetics that allows for chemical control.
It is known that AgRP neurons at the base of the hypothalamus play key roles in hunger and satiety. These neurons are inhibited by feeding and activated by fasting. Artificially exciting these neurons leads to feeding activity, even in mice that have already eaten. Inhibiting these neurons reduces feeding, even in mice that are calorically deficient. Ablating these neurons can cause starvation because the mouse never feels hungry or a need to eat.
Opto-genetic and chemo-genetic studies both show that AgRP is both necessary and sufficient to trigger hunger and feeding. In terms of a wiring diagram, Dr. Lowell’s lab has found a functional node that regulates hunger. They are still figuring out what lies upstream and downstream of the node and how hunger is affected.
Motivational studies describe hunger as a drive to seek a food reward. But the reward value of food depends at least in part on whether one is fasting or fed. The reward value of eating in a fasted state is higher; the reward value of eating more after reaching satiation is lower.
Feeding activates POMC and inhibits AgRP. Fasting activates AgRP and inhibits POMC. Both peptides act to regulate MC4R in the paraventricular nucleus of the hypothalamus (PVH). Activating MC4s reduces hunger, inactivating them increases hunger. PVH lesions or chemical inactivation leads to hyperphagia and obesity. Light or chemical stimulation of AgRP terminals in the PVH lead to increased hunger. As expected, stimulation of MC4R neurons in the PVH increases hunger while inhibition of MC4R neurons increases hunger.
The lateral-parabrachial nucleus is the next step in the hunger mechanism. The L-PBN serves as a relay for interoeptive information from the gut, cardiovascular system, lungs and other organs. Stimulation of MC4R terminals in the L-PBN reduces hunger and inhibition increases hunger. Physiologic signals relayed to the L-PBN from other organs may regulate these hunger and satiety neurons.
“This is an area with therapeutic potential,” Dr. Lowell said. “If we could do this medically, we could devise interesting new kinds of treatments. More work needs to be done.”