Pinpointing the neural pieces of obesity

Obesity is a nationwide epidemic, with more than one-third of adults in the United States qualifying as obese (about 78.6 million people) (Ogden et al., 2014). While there are strategies to prevent obesity, we are in need of better treatment for those struggling with the disease. If we understood how obesity developed, perhaps then we could design interventions to help combat it.

Although obesity is characterized by body mass (that is, a Body Mass Index of 30 or greater is considered obese), how the body expends energy and gains or loses weight is under strict control by the brain (for review, see Zeltser et al., 2012). A brain region of historical and present-day interest is one of the many nuclei that make-up the hypothalamus, namely the paraventricular nucleus (PVH). Sets of PVH neurons defined by the genes they express are known for regulating appetite and energy expenditure, including locomotion, heat production (aka thermogenesis) and oxygen consumption. For example, neurons expressing the melanocortin-4 receptor affect appetite (Garfield et al., 2014), while those expressing oxytocin play a role in energy expenditure (Wu et al., 2012; Sutton et al., 2014).

Now, a new study published in Cell Metabolism, from the lab of Baoji Xu at The Scripps Research Institute in Jupiter, Florida, reports on a formerly unknown population of neurons responsible for energy balance, and whose disruption in mice ultimately leads to obesity.

PVH neurons expressing brain-derived neurotrophic factor (BDNF)

Brain-derived neurotrophic factor (BDNF), a molecule involved in everything from neural circuit development to fear processing, has also been associated with human obesity (see below; Cohen-Cory et al., 2010; Penzo et al., 2015). Hence, the experimenters chose to examine its expression within the PVH. By genetically labeling neurons expressing the Bdnf gene, they found BDNF neurons throughout the PVH and that they were excitatory (i.e. glutamatergic). However, they did not seem to express other genes that mark neurons previously implicated in appetite and energy balance (see Figure). “The population we identified is different from the neuronal populations described in previous studies,” said Xu. But are these neurons players in energy balance?

Losing BDNF leads to overeating and obesity

To tackle this question, the experiments performed two complementary genetic manipulations in mice – deleting BDNF from neurons expressing a transcription factor called SIM1, which encompasses but is not limited to PVH neurons, and by injecting a virus into the PVH to locally rid the region of the molecule. Although BDNF neurons were still likely signaling via glutamate, losing only BDNF eventually caused overeating, lower energy expenditure (less oxygen consumption, locomotion, and thermogenesis in brown fat), and obesity. Interestingly, removing BDNF from the anterior PVH (versus its posterior portion) led to much more severe overeating, suggesting that BDNF neurons in this subregion are more involved in appetite.

Since BDNF seems to be playing such a large role, by what mechanism(s) is it doing so? “It is unclear what it is doing and where it is acting,” said Brad Lowell, a leader in the field whose lab recently showed that PVH neurons expressing the melanocortin-4 receptor are key in appetite control. “For example, retrograde BDNF affects synaptic plasticity while terminal release could affect downstream neurons.”

From brain to fat

A clue to the BDNF’s mechanism may lie in the polysynaptic circuitry of these PVH neurons.  Circuit mapping and labeling experiments pointed to PVH BDNF neurons indirectly increasing brown fat thermogenesis via sympathetic (cholinergic) neurons of the spinal cord that express the receptor for BDNF – TrkB. In BDNF-lacking mice however, these sympathetic neurons were found to be substantially smaller, suggesting that BDNF may be released presynaptically to affect downstream sympathetic neurons. However, these mice had BDNF loss since birth, so its signaling from PVH neurons to the spinal cord may just be needed during development and not necessarily in adulthood.

Another possibility is that BDNF signals in a retrograde fashion – from PVH neurons to those of another nucleus of the hypothalamus, the arcuate nucleus (ARC). The ARC has received much attention recently for housing potential “hunger neurons” (Palmiter, 2015). Polysynaptic circuit mapping indeed showed that the PVH BDNF neurons likely receive input from ARC neurons, although gene expression there did not appear to change.

BDNF connects mice to humans

The obesity resulting from loss of PVH BDNF is artificial. So is BDNF involved in human obesity? “It’s possible,” stated Xu. “Certainly it is a really interesting and important question.” The possibility stems from the fact that BDNF-TrkB mutations are linked to the disease (Han et al., 2008; Yeo et al., 2004). But whether BDNF is recruited in obesity induced by diet, arguably the most common form, remains to be shown. “We’re working on it,” added Xu.

References

Cohen-Cory, S et al. (2010) Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol 70(5):271-88. doi: 10.1002/dneu.20774

Garfield, AS et al. (2015) A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci 18(6):863-71. doi: 10.1038/nn.4011

Han, JC et al. (2008) Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 359(9):918-27. doi: 10.1056/NEJMoa0801119

Juan, JA et al. (2015) Discrete BDNF neurons in the paraventricular hypothalamus control feeding and energy expenditure. Cell Metab 22(1):175-88. doi: 10.1016/j.cmet.2015.05.008

Ogden, CL et al. (2014) Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 311(8):806-14. doi: 10.1001/jama.2014.732

Palmiter, RD. (2015) Hunger logic. Nat Neurosci 18(6):789-91. doi: 10.1038/nn.4032

Penzo, MA et al. (2015) The paraventricular thalamus controls a central amygdala fear circuit. Nature 519(7544):455-9. doi: 10.1038/nature13978

Sutton, AK et al. (2014) Control of food intake and energy expenditure by Nos1 neurons of the paraventricular hypothalamus. J Neurosci 34(46):15306-18. doi: 10.1523/JNEUROSCI.0226-14.2014

Wu, Z et al. (2012) An obligate role of oxytocin neurons in diet induced energy expenditure. PLoS One 7(9):e45167. doi: 10.1371/journal.pone.0045167

Yeo, GS et al. (2004) A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7(11):1187-89. doi: 10.1038/nn1336

Zeltser, LM et al. (2012) Synaptic plasticity in neuronal circuits regulating energy balance. Nat Neurosci 15(10):1336-42. doi: 10.1038/nn.3219

Any views expressed are those of the author, and do not necessarily reflect those of PLOS.

Matthew Soleiman is currently finishing his graduate work at the University of Washington on the cell types and circuitry of the central amygdala. In parallel, he is working as a freelance science writer. You can find him on Twitter as @MatthewSoleiman, or contact him at mtsoleiman@gmail.com.