A Closer Look at the Nerves That Slim Down Fat Cells

When the human body needs extra energy, the brain tells fat cells to release their stores. Now, for the first time, researchers have visualized the nerves that carry those messages from brain to fat tissue. The activation of these nerves in mice, they found, helps the rodents lose weight—an observation that could lead to new slimming treatments for obese people.

These findings were detailed September 24 in the journal Cell, in an article contributed by researchers representing the Instituto Gulbenkian de Ciência (IGC) and Rockefeller University. The article—“Sympathetic Neuro-adipose Connections Mediate Leptin-Driven Lipolysis”—presented evidence that fat tissue is innervated and that direct stimulation of neurons in fat is sufficient to induce fat breakdown.

According to this article, the hormone leptin stimulates lipolysis via sympathetic neurons in fat. Leptin, it is well known, functions as an “adipostat” neuro-endocrine signal that preserves body’s fat mass in a relatively narrow range of variation. Low leptin levels increase appetite and lower basal metabolism, whereas high leptin levels blunt appetite and promote fat breakdown. However, until now, it was largely unknown what circuits close the neuroendocrine loop, such that leptin action in the brain signals back to the fat.

These previously obscure circuits were uncovered by a variety of means. “Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly “enveloping” adipocytes,” wrote the authors of the Cell article. “Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and depletion of white adipose mass. Conversely, genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis, as do knockouts of dopamine β-hydroxylase, an enzyme required for catecholamine synthesis.”

The importance of these techniques was emphasized the ICP researchers. For example, according to Roksana Pirzgalska, co-first author of the study, “Optogenetics made it possible] to locally activate sympathetic neurons in fat pads of mice, and [to observe] fat breakdown and fat mass reduction.”

Study leader and senior co-author Ana Domingos added: “The local activation of these neurons, leads to the release of norepinephrine, a neurotransmitter, that triggers a cascade of signals in fat cells leading to fat hydrolysis. Without these neurons, leptin is unable to drive fat-breakdown.”

The conclusions and future directions are clear according to Ana Domingos: “This result provides new hopes for treating central leptin resistance, a condition in which the brains of obese people are insensitive to leptin.” Senior co-author Jeffrey Friedman, a molecular geneticist at Rockefeller, added: “These studies add an important new piece to the puzzle that enables leptin to induce fat loss.”