Fat is our body’s energy reserve. Fat (adipose) tissue constitutes 20 to 25% of our body mass. There are two types of adipose tissue in our body: white adipose tissue is the one that stores energy, whereas brown adipose tissue generates body heat.

White adipose tissue is made up of adipose cells, or adipocytes, that store lipids in the form of triglycerides. When needed, those stored triglycerides are broken down into free fatty acids and glycerol that are released into the blood to be metabolized such as to meet the energy requirements of our body; this process of fat breakdown is called lipolysis.

Leptin is a hormone that was first described in 1994 by Jeffrey Friedman and colleagues from the Rockefeller University in New York. Leptin tells our brain that we have enough energy stored in our fat cells. It is produced by the adipose cells, released into the bloodstream, and then travels to the brain, where it activates receptors in the hypothalamus to regulate food intake and metabolism.

Leptin plays a major role in weight control. Low leptin levels increase appetite and lower metabolism, whereas high leptin levels suppress appetite and promote fat breakdown. In obesity, a decreased sensitivity to leptin occurs, in a phenomenon known as “leptin resistance”, resulting in an inability to sense satiety despite high energy storage.

Leptin is known to be able to act on brown adipose tissue by increasing sympathetic signaling. Leptin was also suspected to be able to stimulate lipolysis in white adipose tissue since it can lead to fast depletion of fat when administered to mice. However, this had not been demonstrated, and the mechanisms of such hypothetic signaling were unknown. Similarly to brown adipose tissue, the sympathetic nervous system was thought to be the intermediary between the brain and white adipose tissue.

However, whereas many studies had shown that brown adipose tissue is richly innervated by sympathetic neurons, white adipose tissue was regarded as being sparsely innervated; it was even considered that fat cells in this type of tissue might not have direct innervation. Therefore, how the brain could tell the white adipose tissue to break down fat after leptin’s command was mostly a puzzle.

But a study published in Cell has just changed this. A research group from the Gulbenkian Science Institute in Portugal, in collaboration with Jeffrey Friedman’s group, has confirmed that leptin can indeed stimulate lipolysis through the action of the sympathetic nervous system.

The authors showed that white adipose tissue is indeed innervated by the sympathetic neurons. They demonstrated that those fat cells are actually encapsulated by sympathetic neuronal terminals.

Furthermore, they showed that the activation of these sympathetic neurons in fat pads of mice leads to fat breakdown and fat mass reduction. Specifically, the activation of these neurons induces the release of the neurotransmitter norepinephrine (or noradrenaline), that then triggers a sequence of signals that lead to fat hydrolysis. Without the action of sympathetic neurons, leptin is actually unable to promote fat breakdown.

By showing that the direct local stimulation of sympathetic neurons in fat is sufficient to induce fat breakdown, this study suggests that the direct activation of the sympathetic nervous system in adipose tissue may be a strategy for the induction of fat loss.

Therefore, besides contributing to a better understanding of the physiology of leptin’s action, this work opens the door to new therapeutic options for leptin resistance and obesity to arise.

References

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Cannon B, & Nedergaard J (2004). Brown adipose tissue: function and physiological significance. Physiological reviews, 84 (1), 277-359 PMID: 14715917
Friedman JM, Halaas JL (1998). Leptin and the regulation of body weight in mammals. Nature, 395(6704):763-70. PMID: 9796811

Montez JM, Soukas A, Asilmaz E, Fayzikhodjaeva G, Fantuzzi G, & Friedman JM (2005). Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal. Proceedings of the National Academy of Sciences of the United States of America, 102 (7), 2537-42 PMID: 15699332

Münzberg H, & Morrison CD (2015). Structure, production and signaling of leptin. Metabolism: clinical and experimental, 64 (1), 13-23 PMID: 25305050

Pan H, Guo J, & Su Z (2014). Advances in understanding the interrelations between leptin resistance and obesity. Physiology & behavior, 130, 157-69 PMID: 24726399

Zeng W, Pirzgalska RM, Pereira MM, Kubasova N, Barateiro A, Seixas E, Lu YH, Kozlova A, Voss H, Martins GG, Friedman JM, & Domingos AI (2015). Sympathetic Neuro-adipose Connections Mediate Leptin-Driven Lipolysis. Cell, 163 (1), 84-94 PMID: 26406372

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