Sympathetic Neuro-adipose Connections Mediate Leptin-Driven Lipolysis

Abstract

Leptin is a hormone produced by the adipose tissue that acts in the brain, stimulating white fat breakdown. We find that the lipolytic effect of leptin is mediated through the action of sympathetic nerve fibers that innervate the adipose tissue. Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly "enveloping" adipocytes. 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. Thus, neuro-adipose junctions are necessary and sufficient for the induction of lipolysis in white adipose tissue and are an efferent effector of leptin action. Direct activation of sympathetic inputs to adipose tissues may represent an alternative approach to induce fat loss, circumventing central leptin resistance. PAPERCLIP.

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation

“…PAS-leptin altered fuel selection at least partially by a reduction of energy intake but may also operate through direct stimulation of sympathetic nervous system activity [38] or peripheral effects on lipolysis [28][29][30]. In concert with our previous reports [11,14], these findings underline the superiority of PAS-leptin in preclinical research and its potential for therapeutic application.…”

The long road to leptin

“…What are the physiologic and cellular mechanisms by which leptin improves glucose metabolism? Recently, our group has provided direct evidence that leptin reduces fat mass by activating sympathetic efferents to adipose tissue, though the elements of the CNS circuits regulating this have not been fully elucidated (68). However, the cellular mechanisms responsible for leptin metabolic effects on fat, liver, and other tissue have not yet been fully elucidated.…”

Non-adrenergic control of lipolysis and thermogenesis in adipose tissues

“…Thus, in general, there is convincing evidence that the CNS-SNS axis plays a role in modulating lipolysis in adipose tissue. Various hormones secreted by peripheral tissues, such as glucagon-like peptide-1 (GLP-1) and leptin, regulate fat metabolism via the CNS-SNS axis (Lockie et al, 2012;Zeng et al, 2015). Efforts to devise pharmacological treatments for metabolic disease by selectively targeting the CNS-SNS-adipose axis have turned out to be complex.…”

“…The functionality of the sympathetic nerves to activate lipolysis was verified recently in vivo using optogenetic depolarization of the sympathetic nerves projecting into the inguinal subcutaneous white fat depot. Unilateral nerve depolarization stimulated phosphorylation of HSL and reduced fat depot mass when applied chronically (Zeng et al, 2015). Melanocortins signaling via the melanocortin 4 receptor (MC4R) in the central nervous system (CNS) play a key role in regulating SNS activity (Berglund et al, 2014).…”