Fat Homeostasis at the Sympathetic Neuro-Adipose Junction
EU-LIFE Science Newsletter 3/2017
News from the Instituto Gulbenkian de Ciência (IGC), Portugal
Dieting and exercise may not be sufficient to stay lean. Research performed in Ana Domingos’ laboratory at the IGC is deciphering the neurobiological mechanisms underlying obesity. Recently they showed that activation of sympathethic neurons in the adipose tissue burns fat, but their elimination triggers obesity.
Hippocrates defined health homeostasis as the harmonious balance of the elements: blood, phlegm, yellow bile, and black bile. Disease was the systematic disharmony of these elements. In volume VII of Epidemics, Hippocrates hypothesized that the origin of obesity was the imbalance between voluntary food intake and exercise.
This conceptual view of obesity has prevailed for more than to 2 millennia, being altered in 1994 with the discovery of leptin, an adipostatic hormone. Leptin is produced by the adipose tissue, in proportion to its size, and maintains adiposity in a very narrow range of variation. Leptin acts in a neuroendocrine feedback loop between the brain and the adipose tissue. The downstream actions of leptin in the brain include suppression of food intake and stimulation of white fat breakdown, i.e. lipolysis.
Whereas the effect of leptin on food intake has been widely studied, that relating to lipolysis only recently has been tackled. The IGC researchers found that the lipolytic effect of leptin is mediated through the action of sympathetic neurons that innervate the white adipose tissue to locally release norepinephrine. Using intravital two-photon microscopy, they observed that sympathetic nerve fibers establish neuro-adipose junctions, directly enveloping adipocytes. Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and local depletion of white adipose mass. Conversely, local genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis.
More recently, the IGC team developed a method, named BRAINSPAReDT, for ablation of cell lineages outside the brain. Using this method they performed genetic sympathectomy to uncover high susceptibility to obesity, which is independent of food intake. 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 in the brain. The results suggest that direct activation of sympathetic inputs to adipose tissues may represent a rational approach to induce fat mass loss, while circumventing central leptin resistance or drug delivery to the brain. This study was recently published in Nature Communications.
Pereira, M.M.A, Mahú, I., Seixas, E., Martinéz-Sánchez, N., Kubasova, N., Pirzgalska, R.M., Cohen, P., Dietrich, M.O., López, M., Bernardes, G.J.L., Domingos, A.I. (2017) A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. Nature Communications. 8:14967.
Image: Nerve bundles dissected from inguinal fat pad contain sympathetic neurons (TH+, orange). Credits: Roksana Pirzgalska, IGC