White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) and its activation is necessary for lipolysis. WAT parasympathetic innervation is not supported. Fully-executed SNS-norepinephrine (NE)-mediated WAT lipolysis is dependent on β-adrenoceptor stimulation ultimately hinging on hormone sensitive lipase and perilipin A phosphorylation. WAT sympathetic drive is appropriately measured by electrophysiological and neurochemical (NE turnover) in non-human animals and this drive is fat pad-specific preventing generalizations among WAT depots and non-WAT organs. Leptin-triggered SNS-mediated lipolysis is weakly supported, whereas insulin or adenosine inhibition of SNS/NE-mediated lipolysis is strongly supported. In addition to lipolysis control, increases or decreases in WAT SNS drive/NE inhibit and stimulate white adipocyte proliferation, respectively. WAT sensory nerves are of spinal-origin and sensitive to local leptin and increases in sympathetic drive, the latter implicating lipolysis. Transsynaptic viral tract tracer use revealed WAT central sympathetic and sensory circuits including SNS-sensory feedback loops that may control lipolysis.

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Oxytocin (OT) administration elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates, and humans by reducing energy intake and increasing energy expenditure. Although the neurocircuitry underlying these effects remains uncertain, OT neurons in the paraventricular nucleus are positioned to control both energy intake and sympathetic nervous system outflow to interscapular brown adipose tissue (BAT) through projections to the hindbrain nucleus of the solitary tract and spinal cord. The current work was undertaken to examine whether central OT increases BAT thermogenesis, whether this effect involves hindbrain OT receptors (OTRs), and whether such effects are associated with sustained weight loss following chronic administration. To assess OT-elicited changes in BAT thermogenesis, we measured the effects of intracerebroventricular administration of OT on interscapular BAT temperature in rats and mice. Because fourth ventricular (4V) infusion targets hindbrain OTRs, whereas third ventricular (3V) administration targets both forebrain and hindbrain OTRs, we compared responses to OT following chronic 3V infusion in DIO rats and mice and chronic 4V infusion in DIO rats. We report that chronic 4V infusion of OT into two distinct rat models recapitulates the effects of 3V OT to ameliorate DIO by reducing fat mass. While reduced food intake contributes to this effect, our finding that 4V OT also increases BAT thermogenesis suggests that increased energy expenditure may contribute as well. Collectively, these findings support the hypothesis that, in DIO rats, OT action in the hindbrain evokes sustained weight loss by reducing energy intake and increasing BAT thermogenesis.

White adipose tissue (WAT) and brown adipose tissue (BAT) are innervated and regulated by the sympathetic nervous system (SNS). It is not clear, however, whether there are shared or separate central SNS outflows to WAT and BAT that regulate their function. We injected two isogenic strains of pseudorabies virus, a retrograde transneuronal viral tract tracer, with unique fluorescent reporters into interscapular BAT (IBAT) and inguinal WAT (IWAT) of the same Siberian hamsters to define SNS pathways to both. To test the functional importance of SNS coordinated control of BAT and WAT, we exposed hamsters with denervated SNS nerves to IBAT to 4°C for 16-24 h and measured core and fat temperatures and norepinephrine turnover (NETO) and uncoupling protein 1 (UCP1) expression in fat tissues. Overall, there were more SNS neurons innervating IBAT than IWAT across the neuroaxis. However, there was a greater percentage of singly labeled IWAT neurons in midbrain reticular nuclei than singly labeled IBAT neurons. The hindbrain had ~30-40% of doubly labeled neurons while the forebrain had ~25% suggesting shared SNS circuitry to BAT and WAT across the brain. The raphe nucleus, a key region in thermoregulation, had ~40% doubly labeled neurons. Hamsters with IBAT SNS denervation maintained core body temperature during acute cold challenge and had increased beige adipocyte formation in IWAT. They also had increased IWAT NETO, temperature, and UCP1 expression compared with intact hamsters. These data provide strong neuroanatomical and functional evidence of WAT and BAT SNS cross talk for thermoregulation and beige adipocyte formation.

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Brown adipose tissue (BAT) is an important source of thermogenesis which is nearly exclusively dependent on its sympathetic nervous system (SNS) innervation. We previously demonstrated the SNS outflow from brain to BAT using the retrograde SNS-specific transneuronal viral tract tracer, pseudorabies virus (PRV152) and demonstrated the sensory system (SS) inflow from BAT to brain using the anterograde SS-specific transneuronal viral tract tracer, H129 strain of herpes simplex virus-1. Several brain areas were part of both the SNS outflow to, and receive SS inflow from, interscapular BAT (IBAT) in these separate studies suggesting SNS-SS feedback loops. Therefore, we tested whether individual neurons participated in SNS-SS crosstalk by injecting both PRV152 and H129 into IBAT of Siberian hamsters. To define which dorsal root ganglia (DRG) are activated by BAT SNS stimulation, indicated by c-Fos immunoreactivity (IR), we prelabeled IBAT DRG innervating neurons by injecting the retrograde tracer Fast Blue (FB) followed 1 week later by intra-BAT injections of the specific ␤ 3 -adrenoceptor agonist CL316,243 in one pad and the vehicle in the contralateral pad. There were PRV152ϩH129 dually infected neurons across the neuroaxis with highest densities in the raphe pallidus nucleus, nucleus of the solitary tract, periaqueductal gray, hypothalamic paraventricular nucleus, and medial preoptic area, sites strongly implicated in the control of BAT thermogenesis. CL316,243 significantly increased IBAT temperature, afferent nerve activity, and c-Fos-IR in C2-C4 DRG neurons ipsilateral to the CL316,243 injections versus the contralateral side. The neuroanatomical reality of the SNS-SS feedback loops suggests coordinated and/or multiple redundant control of BAT thermogenesis.

ObjectiveMetabolic challenges, such as a cold environment, stimulate sympathetic neural efferent activity to white adipose tissue (WAT) to drive lipolysis, thereby increasing the availability of free fatty acids as one source of fuel for brown adipose tissue (BAT) thermogenesis. WAT is also innervated by sensory nerve fibers that network to metabolic brain areas; moreover, activation of these afferents is reported to increase sympathetic nervous system outflow. However, the endogenous stimuli sufficient to drive WAT afferents during metabolic challenges as well as their functional relation to BAT thermogenesis remain unknown.MethodWe tested if local WAT lipolysis directly activates WAT afferent nerves, and then assessed whether this WAT sensory signal affected BAT thermogenesis in Siberian hamsters (Phodopus sungorus).Results2-deoxyglucose, a sympathetic nervous system stimulant, caused β-adrenergic receptor dependent increases in inguinal WAT (IWAT) afferent neurophysiological activity. In addition, direct IWAT injections of the β3-AR agonist CL316,243 dose-dependently increased: 1) phosphorylation of IWAT hormone sensitive lipase, an indicator of SNS-stimulated lipolysis, 2) expression of the neuronal activation marker c-Fos in dorsal root ganglion neurons receiving sensory input from IWAT, and 3) IWAT afferent neurophysiological activity, an increase blocked by antilipolytic agent 3,5-dimethylpyrazole. Finally, we demonstrated that IWAT afferent activation by lipolysis triggers interscapular BAT thermogenesis through a neural link between these two tissues.ConclusionsThese data suggest IWAT lipolysis activates local IWAT afferents triggering a neural circuit from WAT to BAT that acutely induces BAT thermogenesis.

The primitive neurohypophyseal nonapeptide oxytocin (OXT) has established functions in parturition, lactation, appetite, and social behavior. We have shown that OXT has direct actions on the mammalian skeleton, stimulating bone formation by osteoblasts and modulating the genesis and function of bone-resorbing osteoclasts. We deleted OXT receptors (OXTRs) selectively in osteoblasts and osteoclasts usingCol2.3CreandAcp5Cremice, respectively. Both male and femaleCol2.3Cre+:Oxtrfl/flmice recapitulate the low-bone mass phenotype ofOxtr+/−mice, suggesting that OXT has a prominent osteoblastic action in vivo. Furthermore, abolishment of the anabolic effect of estrogen inCol2.3Cre+:Oxtrfl/flmice suggests that osteoblastic OXTRs are necessary for estrogen action. In addition, the high bone mass inAcp5Cre+:Oxtrfl/flmice indicates a prominent action of OXT in stimulating osteoclastogenesis. In contrast, we found that in pregnant and lactatingCol2.3Cre+:Oxtrfl/flmice, elevated OXT inhibits bone resorption and rescues the bone loss otherwise noted during pregnancy and lactation. However, OXT does not contribute to ovariectomy-induced bone loss. Finally, we show that OXT acts directly on OXTRs on adipocytes to suppress the white-to-beige transition gene program. Despite this direct antibeiging action, injected OXT reduces total body fat, likely through an action on OXT-ergic neurons. Consistent with an antiobesity action of OXT,Oxt−/−andOxtr−/−mice display increased total body fat. Overall, the actions of OXT on bone mass and body composition provide the framework for future therapies for osteoporosis and obesity.