Hypertension in obesity: is leptin the culprit? Stephanie E. Simonds, Michael A. Cowley  Trends in Neurosciences  Volume 36, Issue 2, Pages 121-132 (February 2013) DOI: 10.1016/j.tins.2013.01.004 Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 1 The autonomic nervous system: pathways from the brain to the periphery of the sympathetic and parasympathetic nervous systems. The parasympathetic nerves leave the brain and preganglionic cholinergic parasympathetic nerves (red) (the third, seventh, ninth and tenth cranial nerves, and spinal nerves S2, S3, and S4) innervate target organs. The third (III) parasympathetic preganglionic nerve synapses to the postganglionic parasympathetic nerve in the ciliary (1). The seventh (VII) parasympathetic preganglionic nerve synapses to the postganglionic sympathetic parasympathetic nerve in either the pterygopalatine ganglion (2) or the submandibular region (3). The ninth cranial nerve (IX) parasympathetic preganglionic nerve synapses in the optic ganglia (4). The parasympathetic preganglionic nerve axons of the vagus nerve are long and this leads to the synapses of terminals onto parasympathetic postganglionic synapses (purple) close to target organs. The short parasympathetic postganglionic nerves are also cholinergic and they release acetylcholine at their terminals, propagating the parasympathetic nerve message from the brain. The vagus nerve (cranial nerve X) is a well-studied parasympathetic nerve because it innervates numerous abdominal organs, including esophagus, trachea, heart, lungs, stomach, pancreas, liver, and kidney. It also appears to regulate the activity of white adipose tissue (WAT), although controversy exists about the impact of parasympathetic innervation of WAT [133–135]. The sympathetic nerves arise from the intermediolateral nucleus (IML) of the spine from T1 to L3; the preganglionic sympathetic nerves (blue) are cholinergic. Sympathetic preganglionic nerves are shorter than parasympathetic preganglionic nerves and synapse onto adrenergic sympathetic postganglionic nerves (green) in the sympathetic trunk, a set of ganglia that sit adjacent to the spine. These postganglionic nerves release catecholamine products that act on these target organs. Interestingly, two organs that receive sympathetic inputs, the adrenal and sweat glands, are innervated with acetylcholine acting at muscarinic receptors, rather than with catecholamine as the product. The T5–T9 region synapses sympathetic preganglionic nerves to sympathetic postganglionic nerves in the suprarenal ganglia (celiac ganglia) (5). The T10–T12 sympathetic preganglionic nerves synapse to sympathetic postganglionic nerves in either the aorticorenal (6) or superior mesenteric ganglia (7). The L1–L2 region sympathetic postganglionic nerves synapse to postganglionic sympathetic nerves in the inferior mesenteric ganglia (8). These sympathetic postganglionic nerves innervate many organs in the body, including the heart, kidney, blood vessels, lungs, liver, and pancreas. Sympathetic nerves also innervate (originating from along the sympathetic trunk, depending on the location of the fat deposit in the body) and regulate WAT. Only the sympathetic nervous system regulates the activity of brown adipose tissue (BAT), which is located in multiple small clusters, including thoracic, paraspinal, subclavicular and interscapular regions. Many organs receive both sympathetic and parasympathetic inputs, showing the ability of these systems to regulate homeostasis cooperatively within the body. Trends in Neurosciences 2013 36, 121-132DOI: (10.1016/j.tins.2013.01.004) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 2 Brain circuitry of the parasympathetic nervous system (PSNS). Schematic of major brain nuclei that regulate PSNS efferent tone. The NA and DMX (purple nuclei) are both key regions involved in the activation of the PSNS, especially the vagus nerve (green lines). Several other regions, including the NTS, PVH, aBST, and Prl, send direct inputs (blue lines) to the DMX and NA. The hypothalamus (i.e., The DMH, ARH, VMH, and LH) provides inputs directly into the PVH and NTS and, hence, has the potential to influence parasympathetic output. Leptin receptors (yellow circles), insulin receptors (orange circles), and melanocortin 4 receptors (green circles) are expressed in several of these nuclei. Abbreviations: aBST, anterior bed nucleus of the stria terminalis; ARH, arcuate nucleus of the hypothalamus; DMH, dorsomedial hypothalamus; DMX, dorsal motor nucleus of the hypothalamus; NA, nucleus ambiguous; NTS, nucleus of the solitary tract: PVH, paraventricular hypothalamus: Prl, prelimbic cortex. Trends in Neurosciences 2013 36, 121-132DOI: (10.1016/j.tins.2013.01.004) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 3 Brain circuitry of the sympathetic nervous system. Schematic of major brain nuclei that regulate sympathetic nervous system tone. The IML receives direct inputs from numerous nuclei that contain premotor sympathetic cells (red lines). These regions include the RPa, PVH, RVLM, A5, and LC (dark-pink circles). Other brain regions influence the activity of these regions by sending excitatory and inhibitory inputs. Several of these regions are from the hypothalamus, including the DMH, ARH, VMH, and LH. Extra hypothalamic regions also play critical roles, including the CeA, IL, PBN, and NTS. Leptin receptors (yellow circles), insulin receptors (orange circles), and melanocortin 4 receptors (green circles) are expressed in several of these nuclei. Abbreviations: aBST, anterior bed nucleus of the stria terminalis; ARH, arcuate nucleus of the hypothalamus; A5, A5 adrenergic neurons; CeA, central amygdale; CVLM, caudal ventrolateral medulla; DMH, dorsomedial hypothalamus; IL, infralimbic cortex, IML, intermediolateral nucleus; LC, locus coeruleus; LH, lateral hypothalamus; NA, nucleus ambiguous; NTS, nucleus of the solitary tract; PBN, parabranchial nucleus; PVH, paraventricular hypothalamus; RPa, ralph pallidus; RVLM, rostral ventrolateral medulla; VMH, ventromedial hypothalamus. Trends in Neurosciences 2013 36, 121-132DOI: (10.1016/j.tins.2013.01.004) Copyright © 2013 Elsevier Ltd Terms and Conditions