The authors then spent a significant amount of time investigating what is happening in these GABA-expressing cells in the hypothalamus upon dopamine D2R signaling. They worked out a complicated molecular cascade that gets activated in response to dopamine, which mediates the downstream effects on body weight and brown fat heat production (involving PKA, rpS6, PDE3B). I think if I spent too much time on this, we’d get too lost in the weeds and no one would keep reading. If you’re interested in these details, please read the paper using the link at the beginning of this post!

Additionally, they uncovered that these D2R positive neurons actually act through their modulation of hypocretin/orexin neuron signaling. If you’ve been following the journal club for a while, you should be familiar with this cell type within the hypothalamus (it is my favorite!). When the authors used mice lacking hypocretin/orexin (genetic knockouts), bromocriptine no longer had an effect on metabolism and body weight! Additionally, when they activated GABA neurons using DREADD technology (as described above) along with a drug that inhibits hypocretin/orexin signaling, they no longer observed reductions in body weight or increases in BAT temperature! This strongly suggests that GABA neurons expressing D2R regulate whole body metabolism through their actions on hypocretin/orexin neurons.

All of this is important mechanistic work to understand circuitry underlying homeostatic hunger and energy balance. Following these extensive studies, the researchers took a retrospective approach to examine how another drug that binds the D2R, cabergoline, influences body weight in humans. This drug is not usually prescribed for obesity, but is given to combat a relatively common condition known as hyperprolactinemia as a result of tumors of the pituitary gland. They took data from a group of patients that had been given cabergoline for one year, and assessed body weight changes after 3 months and 12 months. They observed that patients treated with cabergoline experienced little to no side-effects and (on average) lost significant amounts of weight 3 months following starting treatment (see Figure 4). This effect persisted, to a degree, for a year following the start of treatment. They additionally demonstrated that patients had higher resting energy expenditure (similar to the BAT thermogenesis measures in rodents) than before they started treatment. Together , these data suggest that D2R signaling in the hypothalamus promotes weight loss by increasing resting energy expenditure through SNS innervation of brown adipose tissue.