AgRP neurons exert remarkable control over hunger. They are activated when stores are reduced, and once engaged, they induce intense hunger. Of great interest are the means by which AgRP neuron activity is controlled. While circulating hormones like leptin and ghrelin have direct effects on AgRP neurons, AgRP neurons also receive extensive neural input. This latter point has three important implications. First, changes in AgRP neuron activity in response to fasting could primarily be caused by alterations in the strength and number of afferent synapses (i.e. synaptic plasticity). Indeed, an important role for synaptic plasticity has already been established. Second, in addition to effects on plasticity, the fasted state is also likely sensed directly or indirectly by the afferent neurons themselves, with this information then being transmitted to AgRP neurons through the very same synapses. Third, cues other than those related to energy balance could also engage these afferents to bring about rapid changes in AgRP neuron activity. Of note, food-related cues, without any consumption of food, have recently been shown by others, and us, to rapidly reduce AgRP neuron activity. The existence of such rapid, "non-homeostatic" control of AgRP neurons has important implications, and is highly likely to be mediated by afferent neural input. Our goal for this project is to better understand the synaptic and molecular mechanisms by which AgRP neuron activity is controlled.
ARC AgRP neurons are activated by fasting and inhibited by feeding. When turned on, they rapidly and potently drive hunger. ARC POMC neurons, on the other hand, are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and their activity leads to opposite effects - decreased hunger. The antagonistic “yin-yang” functions of these two neurons is a constant feature of essentially all proposed models of homeostatic hunger/satiety regulation. At odds with this widely held view, however, is the finding that opto- and chemo-genetic activation of ARC POMC neurons fails to decrease food intake over a period of less than 8-12 hours of stimulation. Contrast this with the potent effect on hunger observed just minutes following ARC AgRP neuron stimulation. This striking lack of effect strongly suggests that ARC POMC neurons, by themselves, are not the full counterpoint to ARC AgRP neurons. Based on this, we hypothesize the following: A) A functionally important, presently unknown neural component of the ARC-based homeostatic satiety system is missing from current models. B) Excitatory ARC VGLUT2 neurons not expressing POMC provide this missing component and when stimulated / inhibited, they rapidly increase / decrease satiety. C) Reconciling the known important roles of αMSH and MC4Rs as evidenced by genetic studies, with the inability of acute selective stimulation of ARC POMC neurons to rapidly affect hunger, we hypothesize that ARC POMC neurons do not work in isolation but instead decrease hunger by increasing the strength of excitatory synaptic transmission across the ARC VGLUT2 neuron to PVH satiety neuron synapse. We postulate that this occurs via αMSH/MC4R-mediated effects on synaptic plasticity.
Melanocortins, working through MC4Rs, regulate energy balance, but the underlying neural mechanisms have been unknown. POMC neurons release the MC4R agonist, α-MSH, and promote negative energy balance, while AgRP neurons release the antagonist, AgRP, and do the opposite. Consistent with these opposing roles, opto- and chemo-genetic stimulation of POMC neurons causes hypophagia and weight loss, while similar stimulation of AgRP neurons produces hyperphagia and weight gain - with prolonged effects being mediated by AgRP through its action on MC4Rs. Importantly, the α-MSH/MC4R pathway also operates in humans, as evidenced by marked obesity in individuals lacking either α-MSH or MC4Rs. Despite the established importance of MC4Rs in both mice and humans, the neural mechanisms by which they regulate energy balance, and in particular hunger/satiety, have been unknown. Identifying the neuron types and neuronal circuits through which MC4Rs control appetite is the major focus of this project.
Relevant Recent Publications from the Lowell Lab
Fenselau et al., 2017. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nature Neuroscience
Garfield et al., 2015. A neural basis for melanocortin-4 receptor-regulated appetite. Nature Neuroscience
Shah et al., 2014. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. PNAS
Single-Cell RNA-Seq - Cell Types & Genes in Energy Balance
Which neural cell types and genes control appetite and metabolism? How do they respond to metabolic stress and energy imbalance?
These and other questions are currently being addressed in the Lowell Lab through single-cell RNA-Seq. Single-cell RNA-Seq is a transformative way to identify cell types and their transcriptional programs, with genome-wide scope and single-cell resolution. The Lowell Lab currently uses three complementary methods for single-cell RNA-Seq, including (1) manual isolation of labeled populations of interest, (2) single-nuclei RNA-Seq for a dissociation-free profiling, and (3) Drop-seq for high-throughput taxonomy of key brain regions.
Little is known about the neurocircuit and neurobiological bases for regulation of feeding and metabolism, and this has greatly limited progress in understanding and treating obesity and feeding disorders. Lack of knowledge in this area is due, in large part, to complexity within brain regions controlling these processes - namely those that lie within and are connected to the hypothalamus. Each anatomic subregion contains many different types of neurons, each controlling unrelated, opposite or unknown functions. While general information exists regarding connectivity between subregions, this provides little mechanistic insight because the functions of the different neurons within each subregion are complex and/or unknown, and the labeled lines connecting specific upstream neurons to specific downstream neurons are also not known. In essence, we lack a "wiring diagram" for hypothalamic control of behavior and physiology. With recent technological advances, enabled by neuron-specific Cre-expressing mice, it is now possible in a cell-specific fashion to establish connectivity and function. This project utilizes such approaches to delineate the neurocircuitry underlying leptin regulation of energy balance. These studies build upon our discovery that the majority of leptin's anti-obesity effects are mediated by leptin receptors on GABAergic neurons.
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