American scientists reported the discovery of a new population of neurons that are targets for the adipose tissue hormone leptin. They turned out to be neurons of the arcuate nucleus of the hypothalamus that express basonuclein 2. Under the influence of leptin, these neurons directly inhibit AgRP neurons and thereby suppress appetite in mice. The study was published in the journal Nature.
Adipose tissue-derived leptin maintains homeostatic control of adipose tissue mass by regulating food intake and energy balance. It does so by inhibiting AgRP and neuropeptide Y-expressing neurons and activating hypothalamic proopiomelanocortin-expressing neurons (POMC neurons). All of these neurons are located in the arcuate nucleus of the hypothalamus.
In general, two neuronal populations, AgRP neurons and POMC neurons, antagonistically regulate leptin-mediated food intake. However, the functional effects and process dynamics of these neurons differ in several important respects, and several lines of evidence indicate the existence of other leptin-sensitive neuronal populations that may be critical for leptin-mediated control of food intake and body weight.
Researchers led by Jeffrey Friedman of Rockefeller University systematically profiled the transcriptomes of neurons in the arcuate nucleus of the hypothalamus of mice using single-nucleus RNA sequencing. It turned out that one of the clusters contained previously undescribed neurons expressing the leptin receptor. These were neurons expressing basonuclin 2 (BNC2 neurons), a protein of the basonuclin-zinc finger family that is involved in the regulation of mRNA splicing, processing, transcription, and plays an important role in early embryonic development.
To further study the dynamics and function of BNC2 neurons, the scientists bred a line of mice with a knockout of the BNC2 gene. Experiments showed that BNC2 neurons respond to sensory cues associated with food in an experience-dependent manner, and that food consumption further activates these neurons. In the experiment, mice that had been fasting overnight were given food for two or ten minutes. After the food was removed, the activity of BNC2 neurons quickly decreased, and, conversely, it remained high with constant access to food.
Further molecular studies showed that some of the sensory signals that suppress AgRP neurons and reduce appetite after eating are transmitted by BNC2 neurons. Several experiments then demonstrated that leptin increases the activity of BNC2 neurons. They, in turn, directly inhibit the activity of AgRP neurons, which leads to appetite suppression.
Deleting leptin receptors in BNC2 neurons caused excessive appetite and led to obesity in mice. Similar changes were observed when leptin receptor genes were knocked out in AgRP neurons. Notably, the scientists also observed improved glucose tolerance and increased insulin sensitivity in mice after activating BNC2 neurons.
Thus, the scientists conclude that the population of BNC2 neurons in the arcuate nucleus of the hypothalamus directly and rapidly regulates feeding and energy balance. These results add a new important component to the neural circuit responsible for appetite and its disorders, and add to our knowledge of the mechanisms by which leptin regulates this system. Potentially, pharmacological activation of these neurons may have therapeutic value for weight loss.
Previously, we reported that the taste and smell of food induces mitochondrial fragmentation in the liver through the activation of POMC neurons.
