Cutting-edge experiments show that the hormone leptin, which is secreted by fat cells, promotes fat loss by activating the release of catecholamine signalling molecules from neurons wrapped around the fat cells.
Anyone wanting to lose a few extra pounds might well wish that fat could be burnt at the flick of a switch. As Zeng et al.1 report in Cell, they have achieved just that in mice. In doing so, they reveal clues to the mechanism by which the hormone leptin promotes fat loss in mammals.
One of the main functions of one type of fat, white adipose tissue (WAT), is to store lipids. WAT is also the primary source of leptin, which is secreted in response to lipid storage and acts in the brain to reduce body-fat mass2,3. Although many experiments4 have shown that leptin activates lipolysis (lipid breakdown), the mechanisms that underlie this feedback loop are less well defined. In particular, although lipolysis is thought to be under tight control of the brain and the peripheral nervous system4, several key questions remain unanswered. For example, does WAT receive bona fide innervation from the autonomic nervous system (the part of the peripheral nervous system that regulates day-to-day organ function)? And how are fat depots slimmed down when the brain is instructed that fat stores are more than sufficient?
Zeng and colleagues used state-of-the-art techniques to investigate whether the lipolytic effect of leptin is mediated by the autonomic nervous system. Technical innovations5,6 now allow researchers to clear intact organs of lipids, making the organs more transparent and thus amenable to visualization by microscopy. The authors exploited this advance to clear mouse-derived inguinal fat pads (masses of closely packed fat cells close to the hind leg), and then used sophisticated imaging techniques to reconstruct 3D anatomical pictures of the entire tissue7. This reconstruction revealed that thick bundles of neuronal projections called axons cover the surface of the fat pad.
The researchers found that these bundles belong to the sympathetic nervous system — the part of the autonomic nervous system that stimulates the fight-or-flight response, and that is responsible for accelerating heart rate, dilating pupils and activating sweat secretion. Indeed, many of the bundles expressed the enzyme tyrosine hydroxylase, which helps to synthesize catecholamine molecules such as noradrenaline that act as neurotransmitters in the sympathetic nervous system. Zeng and colleagues also showed in vivo that fat cells were located close to nerve fibres that expressed tyrosine hydroxylase. Fat pads were not analysed using electron microscopy, which could have verified whether sympathetic neurons terminate on fat-cell membranes. But these data nonetheless indicate that tyrosine-hydroxylase-expressing axonal projections make contact with some fat cells.
Next, Zeng et al. investigated the relationship between activation of the axon bundles and fat-cell metabolism using optogenetics — a revolutionary technique in which light-sensitive ion-channel proteins are selectively expressed in certain neurons and activate those neurons when exposed to light8. Although the technique is commonly used on the brain, optogenetic experiments on other tissues are often hindered by the fact that neurons outside the brain can have long axons; this means that high levels of light-controlled ion-channel-protein expression are required to drive photoactivation of the distant projections9. Exacerbating this problem, the axons that innervate the inguinal fat pad originate in clusters of neuronal cell bodies that are almost impossible to access for precise, chronic light stimulation.
The authors overcame these technical challenges by using genetic techniques to specifically target sympathetic axons, and locally modulated the activity of axons innervating the fat pad. As a compelling verification of the method's effectiveness, illuminating the inguinal fat had the same effect as treating mice with leptin — levels of noradrenaline increased, as did phosphorylation (an activating molecular modification) of hormone-sensitive lipase (HSL), an enzyme that the authors used as a measure of leptin-elicited lipolysis. Daily optogenetic activation of axons over several weeks reduced fat mass. Conversely, disrupting neuronal input to the fat pad genetically, surgically or pharmacologically almost completely blocked leptin-evoked HSL phosphorylation. This indicates clearly that leptin-triggered lipolysis depends on activation of the sympathetic neurons that project to fat (Fig. 1).
To investigate the molecular mechanism underlying this response to leptin, Zeng et al. analysed genetically engineered mice in which catecholamine signalling was blocked. The mice lacked either an enzyme involved in noradrenaline synthesis or isoforms of noradrenaline-receptor proteins called β-adrenoceptors, which are expressed by fat cells. Although leptin treatment resulted in phosphorylated HSL and fat loss in wild-type mice, these effects were attenuated in both types of mutant. Notably, mice lacking the β-adrenoceptor isoforms β1 and β2 showed more lipase phosphorylation and whole-body fat loss than those lacking β1, β2 and β3, consistent with a study10 that pointed to a dominant role for β3 receptors in lipolysis.
Finding that sympathetic neurons innervate WAT and mediate leptin-stimulated lipolysis is not surprising. However, Zeng and colleagues' study fills a gap in our understanding of precisely how organisms respond to an abundance of leptin. Their work also specifically demonstrates that sympathetic neurons projecting to WAT are a central trigger for leptin-mediated lipolysis.
Of course, questions arise from these findings. Leptin is thought to signal through several brain areas11, but it remains unclear which neuronal networks sense increased blood leptin concentrations and control sympathetic relay stations to ultimately regulate lipolysis and fat mass. Notably, only half of the nerve fibres found in WAT expressed tyrosine hydroxylase, and the authors did not analyse the other half, nor the characteristics of the fat cells that the neurons innervate. Although their identities remain elusive, these neurons and fat cells hold the potential for further exciting discoveries. Future experiments should define the key brain areas that control sympathetic traffic to WAT and the molecular circuitry that controls lipolysis downstream of these effectors.
Zeng et al. estimated that tyrosine-hydroxylase-expressing neurons envelop between 3 and 12% of fat cells, a relatively sparse coverage. Nonetheless, the fact that optogenetic activation markedly increased lipolysis indicates that catecholamine signalling through neuro-adipose junctions has an important role in the control of lipid homeostasis. Given that leptin resistance is a common feature of obesity, it is to be hoped that this study will fuel further dissections of the brain–fat axis. It might also open a door to assessing the therapeutic potential of controlling catecholamine signalling in fat.
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