Leptin-sensitive sensory nerves innervate white fat

Abstract

Leptin, the primary white adipose tissue (WAT) adipokine, is thought to convey lipid reserve information to the brain via the circulation. Because WAT responds to environmental/internal signals in a fat pad-specific (FPS) manner, systemic signals such as leptin would fail to communicate such distinctive information. Saturation of brain leptin transport systems also would fail to convey increased lipid levels beyond that point. WAT possesses sensory innervation exemplified by proven sensory-associated peptides in nerves within the tissue and by viral sensory nerve-specific transneuronal tract tracer, H129 strain of herpes simplex virus 1 labeling of dorsal root ganglia (DRG) pseudounipolar neurons, spinal cord and central sensory circuits. Leptin as a paracrine factor activating WAT sensory innervation could supply the brain with FPS information. Therefore, we tested for and found the presence of the long form of the leptin receptor (Ob-Rb) on DRG pseudounipolar neurons immunohistochemically labeled after injections of Fluorogold, a retrograde tract tracer, into inguinal WAT (IWAT). Intra-IWAT leptin injections (300 ng) significantly elevated IWAT nerve spike rate within 5 min and persisted for at least 30 min. Intra-IWAT leptin injections also induced significant c-Fos immunoreactivity (ir), indicating neural activation across DRG pseudounipolar sensory neurons labeled with Fluorogold IWAT injections. Intraperitoneal leptin injection did not increase c-Fos-ir in DRG or the arcuate nucleus, nor did it increase arcuate signal transducer and activator of transcription 3 phosphorylation-ir. Collectively, these results strongly suggest that endogenous leptin secreted from white adipocytes functions as a paracrine factor to activate spinal sensory nerves innervating the tissue.

Short and long sympathetic-sensory feedback loops in white fat

“…Additional supportive neuroanatomical evidence for WAT SS innervation is the presence of classical sensory nerve-associated peptides found in neural fibers innervating WAT such as calcitonin gene-related peptide (38) in laboratory rat (30) and in Siberian hamster WAT (26,53,54) as well as substance P (28,30). In addition, others (25) and we (44) demonstrated the direct innervation of WAT by pseudounipolar dorsal root ganglia (DRG) neurons using conventional retrograde tract tracers administered to Sprague-Dawley rat and Siberian hamster WAT, respectively. Collectively, it is clear that WAT possesses sensory innervation (for review see Refs.…”

“…Previously, we (44,69) and others (25) demonstrated the distribution of the postganglionic SNS and SS innervation of IWAT using conventional retrograde tract tracers, as well as previously defining the SNS outflow from the brain to WAT (e.g., 4, 13, 31, 52, 57, 59) and sensory inflow to the brain from WAT (60) using transneuronal tract tracers. In these separate viral tract tracing studies of the central SNS and SS circuitries, many common areas were revealed suggesting the possibility of neuroanatomical SNS-SS crosstalk across the neuroaxis.…”

“…7-9) and because of our previous studies demonstrating increases in the SNS drive to WAT in response to glucoprivation-induced increase in WAT sensory nerve electrophysiological multiunit activity (60), a well-known WAT lipolytic stimulus (15,21,33,34,63), it appears that WAT sensory nerves are sensitive to some aspect of lipolysis (e.g., free fatty acids or glycerol) or an associated factor of SNS activation in WAT [e.g., prostaglandin E 2 (51)]. In addition, the sensory nerves innervating WAT are sensitive to intra-WAT leptin administration (44,47,56) suggesting a role of these feedback circuits in the control of leptin synthesis/secretion.…”

Neural control of white, beige and brown adipocytes

“…53 In terms of the function of WAT sensory nerves, they are responsive to intra-IWAT injection of leptin, as assessed by c-Fos-ir in the dorsal root ganglion neurons innervating WAT that were previously labeled with Fluorogold, a non-viral retrograde tract tracer. 54 In addition, the multiunit electrophysiological activity of the sensory nerves emanating from IWAT increases in response to these intra-IWAT leptin injections in Siberian hamsters. 54 Similar electrophysiological responses to intra-WAT leptin injection were first reported in laboratory rat EWAT injected with this cytokine.…”

“…54 In addition, the multiunit electrophysiological activity of the sensory nerves emanating from IWAT increases in response to these intra-IWAT leptin injections in Siberian hamsters. 54 Similar electrophysiological responses to intra-WAT leptin injection were first reported in laboratory rat EWAT injected with this cytokine. 55,56 Just as the tips of your fingers respond to pain, temperature, vibration and position, WAT sensory innervation also may respond to several different sensory stimuli including the products of lipolysis and perhaps temperature (for review, see Bartness et al 26,43 ).…”