Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. The hypothalamic nuclei respond to the peptide leptin secreted from adipose tissue to suppress feeding and increase energy expenditure by promoting fat metabolism via sympathetic activity. Another important, but perhaps less appreciated function of central leptin signaling is to elevate peripheral insulin sensitivity. Environmental and genetic risk factors that affect hypothalamic leptin signaling can lead to obesity and type 2 diabetes mellitus (T2DM). Here, we discovered that LIM domain only 4, LMO4, is a novel protein participating in central leptin signaling. In a process strikingly similar to T2DM in humans, CaMKIIα-Cre;LMO4flox/flox mice, which have LMO4 knocked out in the postnatal brain including the hypothalamus, develop visceral adiposity, reduced insulin sensitivity, obesity and diabetes when fed with regular chow. Central leptin signaling was significantly lost in key hypothalamic nuclei of mutant mice. Caloric restriction prevents obesity but not insulin resistance in these mice. Taken together, our results suggest that LMO4 function in the brain is required for central leptin signaling to control fat metabolism and peripheral insulin sensitivity.

Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. The hypothalamic nuclei respond to the peptide leptin secreted from adipose tissue to suppress feeding and increase energy expenditure by promoting fat metabolism via sympathetic activity. Another important, but perhaps less appreciated function of central leptin signaling is to elevate peripheral insulin sensitivity. Environmental and genetic risk factors that affect hypothalamic leptin signaling can lead to obesity and type 2 diabetes mellitus (T2DM). Here, we discovered that LIM domain only 4, LMO4, is a novel protein participating in central leptin signaling. In a process strikingly similar to T2DM in humans, CaMKIIα-Cre;LMO4flox/flox mice, which have LMO4 knocked out in the postnatal brain including the hypothalamus, develop visceral adiposity, reduced insulin sensitivity, obesity and diabetes when fed with regular chow. Central leptin signaling was significantly lost in key hypothalamic nuclei of mutant mice. Caloric restriction prevents obesity but not insulin resistance in these mice. Taken together, our results suggest that LMO4 function in the brain is required for central leptin signaling to control fat metabolism and peripheral insulin sensitivity.

Thesis (Ph. D.)--University of Toledo, 2009. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences (Cancer Biology)." Title at OhioLINK ETD site: Investigation of common bases of sympathetic nervous system and neuroblastoma development. Title from title page of PDF document. Includes bibliographical references (p. 72-75, 119-125, 152-192).

Thesis (M.S.)--University of Delaware, 2009. / Principal faculty advisor: William B. Farquhar, Dept. of Health, Nutrition, & Exercise Sciences. Includes bibliographical references.

The gastrointestinal (GI) tract is subject to regulation by several neuronal networks, one of which is the sympathetic nervous system (SNS). Inflammatory bowel diseases (IBD), most importantly Crohn’s disease and ulcerative colitis, are chronic diseases of the GI tract that result in such functional symptoms as abdominal pain and diarrhea. These symptoms suggest an important role for dysregulation of the SNS in IBD, since this branch of the autonomic nervous system aids in regulation of blood flow, secretion and motility. Inflammatory cytokines that are elevated in the serum and tissue of IBD patients can have wide-ranging effects on neuronal function in vitro, and may be responsible for the functional alterations observed in vivo. With these neuronal alterations in mind, we hypothesized that interleukin-17, a novel cytokine with a central role in the pathogenesis of IBD, modulates the properties of sympathetic neurons innervating the gastrointestinal tract. Using electrophysiological techniques and Ca2+ imaging, we examined the effect of IL-17 on currents passing through voltage-gated Ca2+ channels in neurons from the superior mesenteric ganglion, which innervates the gut, and found that IL-17 inhibited these currents. In parallel, we found that IL-17 enhances the growth of sympathetic neurites in vitro. These effects depend upon activation of the nuclear factor κB (NF-κB) pathway, and do not appear to require glial cells. Therefore, dysregulated neural function during IBD may be due to direct effects of IL-17 on sympathetic neurons. / Thesis (Master, Physiology) -- Queen's University, 2009-09-03 11:33:53.63

Sympathetic catecholamines and co-transmitters released within the gastrointestinal (GI) tract provide dynamic regulation of gut motility, fluid secretion, blood flow and immune cell function. Pathological GI inflammation in patients with inflammatory bowel diseases (IBD) evokes functional and structural plasticity in sympathetic neurons that innervate the gut, which may contribute to symptom generation. The mechanisms responsible for aberrant sympathetic behaviour during colonic inflammation remain elusive, though evidence points to a role for mediators of the mucosal immune response. Interleukin (IL)-17 is the principal cytokine of the novel TH17 lineage of helper T cells. Based on mounting clinical, genetic and experimental evidence, IL-17 is thought to play a pivotal role in the immunopathogenesis of IBD. However, nothing is known of the contribution of IL-17 to sympathetic neuroplasticity during chronic inflammatory disease. We hypothesized that remodelling of postganglionic sympathetic axons occurs in response to exposure of axons to the inflamed colonic milieu and that IL-17 serves as the primary mediator of this neuroanatomical remodelling. An increase in tyrosine hydroxylase (TH) immunoreactivity, a marker of sympathetic axons, was observed in the muscularis externae and mucosae of colons from mice subjected to acute and chronic models of dextran sulphate sodium (DSS)-induced colitis. In parallel, we found markedly elevated levels of IL-17 in the serum and colonic tissues of mice with colitis. To investigate whether the colitis microenvironment promoted axonal growth, distal neurites of adult sympathetic neurons from the superior mesenteric ganglion (SMG) were incubated in supernatant collected from explant cultures of inflamed colon. Colitis supernatant enhanced neurite outgrowth from gut-projecting SMG neurons compared to supernatants from control colon. Importantly, this effect was abrogated following the addition of IL-17-neutralising antiserum to cultures. Moreover, IL-17 increased the morphological complexity of SMG neurites in vitro while none of the other inflammatory cytokines known to be elevated during IBD had a similar effect. These findings suggest a novel role for IL-17 as a mediator of sympathetic neuroanatomical plasticity during colonic inflammation. Whether this contributes to the functional deficits and chronic inflammatory response that occurs in the GI tract during IBD remains to be determined. / Thesis (Master, Physiology) -- Queen's University, 2011-08-10 09:40:13.514

A single-blinded, randomized controlled study was conducted, enrolling thirty-six healthy adults who had not recently participated in forearm strengthening or occupations/hobbies involving repeated forceful wrist motion. A fatiguing wrist extension exercise protocol was completed to induce delayed onset muscle soreness (DOMS). Group one received no treatment. Group two received acupuncture (ACU). Group three received sham acupuncture (S-ACU) with non-penetrating needles. Outcomes included grip strength, visual analogue scale for pain (VAS) and pain pressure threshold (PPT). Skin conductance (SC), skin temperature (ST) and perfusion (BF) were recorded to quantify the sympathetic nervous system response to treatment. The ACU group showed a significant increase in ipsilateral BF and in bilateral SC. The ACU group showed a significant decrease in distal ST bilaterally. The ACU and S-ACU groups showed decreased ipsilateral proximal ST. The exercise protocol did not consistently produce DOMS. The sample size of 36 may not have yielded sufficient statistical power.

Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. The hypothalamic nuclei respond to the peptide leptin secreted from adipose tissue to suppress feeding and increase energy expenditure by promoting fat metabolism via sympathetic activity. Another important, but perhaps less appreciated function of central leptin signaling is to elevate peripheral insulin sensitivity. Environmental and genetic risk factors that affect hypothalamic leptin signaling can lead to obesity and type 2 diabetes mellitus (T2DM). Here, we discovered that LIM domain only 4, LMO4, is a novel protein participating in central leptin signaling. In a process strikingly similar to T2DM in humans, CaMKIIα-Cre;LMO4flox/flox mice, which have LMO4 knocked out in the postnatal brain including the hypothalamus, develop visceral adiposity, reduced insulin sensitivity, obesity and diabetes when fed with regular chow. Central leptin signaling was significantly lost in key hypothalamic nuclei of mutant mice. Caloric restriction prevents obesity but not insulin resistance in these mice. Taken together, our results suggest that LMO4 function in the brain is required for central leptin signaling to control fat metabolism and peripheral insulin sensitivity.

A single-blinded, randomized controlled study was conducted, enrolling thirty-six healthy adults who had not recently participated in forearm strengthening or occupations/hobbies involving repeated forceful wrist motion. A fatiguing wrist extension exercise protocol was completed to induce delayed onset muscle soreness (DOMS). Group one received no treatment. Group two received acupuncture (ACU). Group three received sham acupuncture (S-ACU) with non-penetrating needles. Outcomes included grip strength, visual analogue scale for pain (VAS) and pain pressure threshold (PPT). Skin conductance (SC), skin temperature (ST) and perfusion (BF) were recorded to quantify the sympathetic nervous system response to treatment. The ACU group showed a significant increase in ipsilateral BF and in bilateral SC. The ACU group showed a significant decrease in distal ST bilaterally. The ACU and S-ACU groups showed decreased ipsilateral proximal ST. The exercise protocol did not consistently produce DOMS. The sample size of 36 may not have yielded sufficient statistical power.

Corticospinal and intracortical excitability are excitability measures of the central nervous system responsible for motor generation, and are studied for their contribution to fine motor skill execution and learning. Since the need for proper execution of fine motor skills is ever-present and necessary for everyday life, identification of physiological pathways that may disrupt or enhance corticospinal and intracortical excitability is an important research topic. This thesis investigates the effects of baroreceptor unloading on corticospinal and intracortical excitability during various motor tasks. Baroreceptor unloading is a physiological response to common hemodynamic stress (e.g. hypovolemia and orthostasis). The motor tasks investigated are complete muscular relaxation, individual isometric low-force contraction of a muscle, and an isometric co-contraction of a muscle in a joint-stabilizing task. The effects of baroreceptor unloading on corticospinal and intracortical excitability appear to be very task specific. The results are discussed in view of available pharmacological and physiological research, and potential neural pathways for the observed effects are suggested. The overall conclusion is that baroreceptor unloading increases corticospinal excitability and decreases intracortical inhibition in a resting muscle, does not produce any observable effects during individual muscle activity, and decreases corticospinal excitability during joint-stabilizing co-contraction.