Abstract
Brown adipose tissue (BAT) contributes to energy homeostasis via nonshivering thermogenesis.
The BAT is densely innervated by the sympathetic nervous system (SNS) and activity
of pre-autonomic neurons modulates the sympathetic outflow. Leptin, an adipocyte hormone,
alters energy homeostasis and thermogenesis of BAT via several neuronal circuits;
however, the cellular effects of leptin on interscapular BAT (iBAT)-related neurons
in the hypothalamus remain to be determined. In this study, we used pseudorabies virus
(PRV) to identify iBAT-related neurons in the paraventricular nucleus (PVN) of the
hypothalamus and test the hypothesis that iBAT-related PVN neurons are modulated by
leptin. Inoculation of iBAT with PRV in leptin receptor reporter mice (Lepr:EGFP)
demonstrated that a population of iBAT-related PVN neurons expresses Lepr receptors.
Our electrophysiological findings revealed that leptin application caused hyperpolarization
in some of iBAT-related PVN neurons. Bath application of leptin also modulated excitatory
and inhibitory neurotransmission to most of iBAT-related PVN neurons. Using channel
rhodopsin assisted circuit mapping we found that GABAergic and glutamatergic Lepr-expressing
neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA) project
to PVN neurons; however, connected iBAT-related PVN neurons receive exclusively inhibitory
signals from Lepr-expressing dDMH/DHA neurons.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Autonomic Neuroscience: Basic and ClinicalAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- 20 years of leptin: connecting leptin signaling to biological function.J. Endocrinol. 2014; 223: T25-T35
- Stimulation of the paraventricular nucleus with glutamate activates interscapular brown adipose tissue thermogenesis in rats.Brain Res. 1990; 508: 152-155
- Divergence of melanocortin pathways in the control of food intake and energy expenditure.Cell. 2005; 123: 493-505
- CNS origins of the sympathetic nervous system outflow to brown adipose tissue.Am. J. Phys. 1999; 276: R1569-R1578
- SCN efferents to peripheral tissues: implications for biological rhythms.J. Biol. Rhythm. 2001; 16: 196-204
- Sympathetic and sensory innervation of brown adipose tissue.Int. J. Obes. 2010; 34: S36-S42
- Glutamatergic drive facilitates synaptic inhibition of dorsal vagal motor neurons after experimentally induced diabetes in mice.J. Neurophysiol. 2016; 116: 1498-1506
- The suprachiasmatic nucleus balances sympathetic and parasympathetic output to peripheral organs through separate preautonomic neurons.J. Comp. Neurol. 2003; 464: 36-48
- Leptin receptor signaling in Sim1-expressing neurons regulates body temperature and adaptive thermogenesis.Endocrinology. 2019; 160: 863-879
- Bilateral lesion of hypothalamic paraventricular nucleus abolishes fever induced by endotoxin and bradykinin in rats.Ann. N. Y. Acad. Sci. 1998; 856: 294-297
- Dual viral transneuronal tracing of central autonomic circuits involved in the innervation of the two kidneys in rat.J. Comp. Neurol. 2004; 471: 462-481
- Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure.J. Comp. Neurol. 2003; 460: 303-326
- Practical considerations for the use of pseudorabies virus in transneuronal studies of neural circuitry.Neurosci. Biobehav. Rev. 1998; 22: 685-694
- Pseudorabies virus infection of the rat central nervous system: ultrastructural characterization of viral replication, transport, and pathogenesis.J. Neurosci. 1993; 13: 2515-2539
- Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat.Neuron. 1999; 24: 155-163
- Selective enhancement of synaptic inhibition by hypocretin (orexin) in rat vagal motor neurons: implications for autonomic regulation.J. Neurosci. 2003; 23: 3844-3854
- Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve.J. Physiol. 2004; 559: 923-938
- Convergent neuronal projections from paraventricular nucleus, parabrachial nucleus, and brainstem onto gastrocnemius muscle, white and brown adipose tissue in male rats.J. Comp. Neurol. 2019; 527: 2826-2842
- Distributions of leptin receptor mRNA isoforms in the rat brain.J. Comp. Neurol. 1998; 395: 535-547
- Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance.J. Neurosci. 2011; 31: 12189-12197
- Unilaterality of the sympathetic innervation of each pad of rat interscapular brown adipose tissue.Can. J. Physiol. Pharmacol. 1982; 60: 107-113
- Sympathetic innervation of the interscapular brown adipose tissue in mouse.Ann. N. Y. Acad. Sci. 2019; 1454: 3-13
- Glycinergic neurotransmission in the rostral ventrolateral medulla controls the time course of baroreflex-mediated sympathoinhibition.J. Physiol. 2019; 597: 283-301
- Transient receptor potential vanilloid type 1-dependent regulation of liver-related neurons in the paraventricular nucleus of the hypothalamus diminished in the type 1 diabetic mouse.Diabetes. 2012; 61: 1381-1390
- Overactivity of liver-related neurons in the paraventricular nucleus of the hypothalamus: electrophysiological findings in db/db mice.J. Neurosci. 2017; 37: 11140-11150
- Electrophysiological analysis of circuits controlling energy homeostasis.Mol. Neurobiol. 2012; 45: 258-278
- Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 355-360
- Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity.Mol. Endocrinol. 2010; 24: 2366-2381
- Synaptic and morphologic properties in vitro of premotor rat nucleus tractus solitarius neurons labeled transneuronally from the stomach.J. Comp. Neurol. 2003; 464: 525-539
- Receptor-mediated regional sympathetic nerve activation by leptin.J. Clin. Invest. 1997; 100: 270-278
- Sympathetic and cardiorenal actions of leptin.Hypertension. 1997; 30: 619-623
- Effects of leptin on corticotropin-releasing factor (CRF) synthesis and CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ob) mice.Endocrinology. 1998; 139: 1524-1532
- Organization of sympathetic innervation of interscapular brown adipose tissue in the mouse.J. Comp. Neurol. 2022; 530: 1363-1378
- Activity of cardiorespiratory networks revealed by transsynaptic virus expressing GFP.J. Neurophysiol. 2001; 85: 435-438
- Reduced GABAergic inhibition of kidney-related PVN neurons in streptozotocin-treated type 1 diabetic mouse.J. Neurophysiol. 2013; 110: 2192-2202
- Hypothalamic control of energy metabolism via the autonomic nervous system.Ann. N. Y. Acad. Sci. 2010; 1212: 114-129
- GABAergic RIP-cre neurons in the arcuate nucleus selectively regulate energy expenditure.Cell. 2012; 151: 645-657
- Leptin receptor signaling and action in the central nervous system.Obesity (Silver Spring). 2006; 14: 208S-212S
- Neurosecretory and non-neurosecretory parvocellular neurones of the hypothalamic paraventricular nucleus express distinct electrophysiological properties.J. Neuroendocrinol. 2002; 14: 929-932
- Voltage-gated currents distinguish parvocellular from magnocellular neurones in the rat hypothalamic paraventricular nucleus.J. Physiol. 2000; 523: 193-209
- Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296: R831-R843
- Cardiovascular responses evoked by leptin acting on neurons in the ventromedial and dorsomedial hypothalamus.Hypertension. 2003; 42: 488-493
- Pseudorabies virus infection alters neuronal activity and connectivity in vitro.PLoS Pathog. 2009; 5e1000640
- Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization.FEBS Lett. 1996; 387: 113-116
- Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats.Diabetes. 1999; 48: 287-291
- Interaction between TRPV1-expressing neurons in the hypothalamus.J. Neurophysiol. 2019; 121: 140-151
- Central nervous system regulation of brown adipose tissue.Compr Physiol. 2014; 4: 1677-1713
- Structure, production and signaling of leptin.Metabolism. 2015; 64: 13-23
- The geometry of leptin action in the brain: more complicated than a simple ARC.Cell Metab. 2009; 9: 117-123
- Effects of leptin on hypothalamic arcuate neurons in wistar and zucker rats: an in vitro study.Exp. Biol. Med. (Maywood). 2003; 228: 1162-1167
- Brain-liver connections: role of the preautonomic PVN neurons.Am. J. Physiol. Endocrinol. Metab. 2016; 310: E183-E189
- The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat.Neuroscience. 2002; 110: 515-526
- Optogenetic activation of leptin- and glucose-regulated GABAergic neurons in dorsomedial hypothalamus promotes food intake via inhibitory synaptic transmission to paraventricular nucleus of hypothalamus.Mol. Metab. 2016; 5: 709-715
- Role of leptin in energy expenditure: the hypothalamic perspective.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2017; 312: R938-r947
- Leptin depolarizes rat hypothalamic paraventricular nucleus neurons.Am. J. Phys. 1998; 274: R1468-R1472
- Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake.Mol. Metab. 2014; 3: 681-693
- Metabolic syndrome: a sympathetic disease?.Lancet Diabetes Endocrinol. 2015; 3: 148-157
- Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus.elife. 2020; 9
- Pseudorabies virus expressing enhanced green fluorescent protein: a tool for in vitro electrophysiological analysis of transsynaptically labeled neurons in identified central nervous system circuits.Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 9264-9269
- Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008; 295: R417-R428
- Electrophysiological and morphological properties of pre-autonomic neurones in the rat hypothalamic paraventricular nucleus.J. Physiol. 2001; 537: 161-177
- The paraventricular nucleus of the hypothalamus: cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde fluorescence double-labeling methods.J. Comp. Neurol. 1980; 194: 555-570
- Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms.Neuroendocrinology. 1980; 31: 410-417
- Separate neurons in the paraventricular nucleus project to the median eminence and to the medulla or spinal cord.Brain Res. 1980; 198: 190-195
- Electrophysiological properties of neurones in the region of the paraventricular nucleus in slices of rat hypothalamus.J. Physiol. 1991; 434: 271-293
- Relevance of sympathetic nervous system activation in obesity and metabolic syndrome.J. Diabetes Res. 2015; 2015341583
- Sympathetic innervation of the mouse kidney and liver arising from prevertebral ganglia.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2021; 321: R328-R337
- Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons.Neuron. 2011; 71: 142-154
- Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue.Endocrinology. 2007; 148: 1550-1560
- Leptin and its receptors.J. Chem. Neuroanat. 2014; 61–62: 191-199
- Rapid inhibition of neurons in the dorsal motor nucleus of the vagus by leptin.Endocrinology. 2007; 148: 1868-1881
- Presynaptic ionotropic glutamate receptors modulate GABA release in the mouse dorsal motor nucleus of the vagus.Neuroscience. 2015; 308: 95-105
- Preoptic leptin signaling modulates energy balance independent of body temperature regulation.elife. 2018; 7
- Glutamatergic preoptic area neurons that express leptin receptors drive temperature-dependent body weight homeostasis.J. Neurosci. 2016; 36: 5034-5046
- Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits.J. Neurosci. 2011; 31: 1873-1884
- Regulation of leptin receptor-expressing neurons in the brainstem by TRPV1.Physiol Rep. 2014; 2
Article info
Publication history
Published online: December 13, 2022
Accepted:
December 8,
2022
Received in revised form:
November 14,
2022
Received:
July 8,
2022
Identification
Copyright
© 2022 Elsevier B.V. All rights reserved.
