Post by: Amanda McFarlan
What's the science?
The paraventricular nucleus of the hypothalamus contains a population of neurons expressing the SIM1 protein that have been shown to be critical in regulating feeding behaviour and satiety (feeling full). Neurons expressing the melanocortin-4 receptor (MC4R) were the first subset of SIM1-expressing neurons to be identified for their role in mediating satiety. However, previous studies have shown that inhibition of MC4R-expressing neurons causes increased appetite that only accounts for approximately half of that observed with inhibition of all SIM1-expressing neurons. Thus, there may be an unidentified population of SIM1-expressing cells, anatomically distinct from MC4R-expressing neurons, that also play a role in mediating satiety. This week in the Neuron, Li and colleagues investigated the role of prodynorphin (PYDN)-expressing neurons in the paraventricular hypothalamus in regulating satiety and bodyweight.
How did they do it?
The authors performed histological analysis in transgenic mice to investigate whether PDYN-expressing neurons and MC4R-expressing neurons were distinct cell populations within the paraventricular hypothalamus, and to determine whether PDYN-expressing neurons also expressed SIM1. Next, they explored how PDYN-expressing neurons affect satiety compared to MC4R-expressing neurons and SIM1-expressing neurons. To do this, they targeted the expression of an inhibitory DREADD (Designer Receptors Exclusively Activated by Designer Drugs) to PDYN-expressing neurons, MC4R-expressing neurons or SIM1-expressing neurons in the paraventricular hypothalamus and then observed the effect of inhibiting these neuronal populations on food consumption during a time of low caloric intake (the light cycle for mice).
Next, the authors investigated the impact of long-term inhibition of PDYN-expressing neurons, MC4R-expressing neurons and both neuronal populations together on food consumption and bodyweight. They targeted either a tetanus toxin (to inhibit synaptic release) or a control virus (non-toxic) to each of the neuronal populations and measured changes in food intake and bodyweight over a one-month period. Next, they identified the brain areas that were innervated by PDYN-expressing neurons by injecting a Cre-dependent anterograde tracer into the paraventricular hypothalamus of a PDYN-Cre transgenic mouse. They used whole-cell recordings and Channelrhodopsin-2-assisted circuit mapping (CRACM) to assess glutamatergic transmission between PDYN-expressing neurons and their downstream connections. Finally, they used optogenetics to either increase or suppress the activity of PDYN-expressing neuronal terminals in the parabrachial complex to investigate the role of this circuit (PDYN-expressing neurons >> parabrachial complex) on food intake and satiety.
What did they find?
The authors determined that nearly all PDYN-expressing neurons also expressed SIM1, but not MC4R, suggesting that PDNY-expressing neurons are an anatomically distinct subset of SIM1-expressing cells. Then, they showed that chemogenetic inhibition of PDNY, MC4R and SIM1-expressing neurons caused an increase in food consumption compared to controls, and the effect of inhibiting PDYN or MC4R-expressing neurons was ~half as great as inhibiting SIM1-expressing neurons. Simultaneous chemogenetic inhibition of both PDNY and MC4R-expressing neurons, increased food intake to a level that was comparable to that observed with inhibition of SIM1-expressing neurons. These findings suggest that PDNY and MC4R-expressing neurons are two functionally independent subpopulations of SIM1-expressing neurons, that together, account for the majority of SIM1-mediated satiety. In addition, the authors found that long-term inhibition of PDYN- expressing neurons caused an increased appetite and a progressive increase in body weight compared to controls.
Next, the authors determined that PDYN-expressing neurons innervated and formed strong glutamatergic connections with neurons in a subregion of the parabrachial complex; this subregion was different than the subregion preferred by MC4R neurons. The results suggest that the pathway from PDNY-expressing neurons to parabrachial complex might be implicated in regulating satiety. Finally, they determined that optogenetic activation of PDNY-expressing neuronal terminals in the parabrachial complex decreased food intake, suggesting that the parabrachial complex is involved in regulating food intake. Conversely, they revealed that optogenetic inhibition of these neuronal terminals increased food intake, suggesting that the parabrachial complex is also necessary for satiety.
What's the impact?
This is the first study to identify a novel subpopulation of SIM1-positive neurons in the paraventricular hypothalamus, expressing PDYN, that are anatomically and functionally independent from MC4R-expressing neurons. These PDYN-expressing neurons were shown to play a key role in regulating feeding behaviour and satiety. Notably, PDYN and MC4R-expressing neurons were shown to have an additive effect that accounted for the totality of SIM1-expressing neuron-mediated satiety. This study has provided insight into the circuitry underlying feeding behaviour and satiety and may be critical in understanding how to better treat conditions such as obesity.
Li et al. The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits. Neuron (2019).Access the original scientific publication here.