The Function of Intestinal Afferent Neurons in Regulating Satiety During Health and Obesity

Background and aim: Within the gastrointestinal tract, vagal afferents regulate satiety and food intake via chemical and mechanical mechanisms. Cysteinyl Leukotrienes (CysLTs) are lipid mediators that are believed to regulate food intake and body weight. However, the involvement of vagal afferents in this effect remains to be established. Conversely, Glucagon like peptide-1 (GLP-1) is a satiety and incretin peptide hormone. The effect of obesity on GLP-1 mediated gut-brain signaling has yet to be investigated. Since intestinal vagal afferents’ activity is reduced during obesity, it is intriguing to investigate their responses to GLP-1 in such conditions. Methods: Extracellular recordings were performed on intestinal afferents from normal C57Bl6, low fat fed (LFF), and high fat fed (HFF) mice. To examine the effect on neuronal calcium signaling, calcium-imaging experiments were performed on isolated nodose ganglion neurons. Food intake experiments were conducted using LFF and HFF mice. Oral glucose tolerance tests (OGTT) were carried out. Whole cell patch clamp recordings were performed on nodose ganglion neurons from A) normal C57Bl mice to test the effect of CysLTs on membrane excitability, B) LFF and HFF mice to examine GLP-1 effect on membrane excitability during obesity. c-Fos immunohistochemical techniques were performed to measure the level of neuronal activation in the brainstem of both LFF and HFF mice in response to Ex-4. Results: CysLTs increased intestinal afferent firing rate and mechanosensitivity. In single nodose neuron experiments, CysLTs increased excitability. The GLP-1 agonist Ex-4 significantly decreased food intake in LFF but not HFF mice. However, Ex-4 markedly attenuated the rise in blood glucose in both LFF and HFF mice. The observed increase in nerve firing and mechanosensitivity following the application of GLP-1 and Ex-4 was abolished in HFF mice. Cell membrane excitability was significantly increased by Ex-4 in nodose from LFF but not HFF mice. Ex-4 significantly increased the number of activated neurons in the NTS area of LFF mice but not in their HFF counterparts. Conclusion: The previous observations indicate that the role CysLTs play in regulating satiety is likely to be vagally mediated. Also that satiety, but not incretin, effects of GLP-1 are impaired during obesity.

SCAPHOID AND LUNATE CARPAL MECHANICS OVER THE SPECTRUM OF HEALTHY FUNCTION

When ligaments within the wrist are damaged, the resulting loss in range of motion and grip strength can lead to reduced earning potential and restricted ability to perform important activities of daily living. Left untreated, ligament injuries ultimately lead to arthritis and chronic pain. Surgical repair can mitigate these issues but current procedures are often non-anatomic and unable to completely restore the wrist’s complex network of ligaments. An inability to quantitatively assess wrist function clinically, both before and after surgery, limits the ability to assess the response to clinical intervention. Previous work has shown that bones within the wrist move in a similar pattern across people, but these patterns remain challenging to predict and model. In an effort to quantify and further develop the understanding of normal carpal mechanics, we performed two studies using 3D in vivo carpal bone motion analysis techniques. For the first study, we measured wrist laxity and performed CT scans of the wrist to evaluate 3D carpal bone positions. We found that through mid-range radial-ulnar deviation range of motion the scaphoid and lunate primarily flexed and extended; however, there was a significant relationship between wrist laxity and row-column behaviour. We also found that there was a significant relationship between scaphoid flexion and active radial deviation range of motion. For the second study, an analysis was performed on a publicly available database. We evaluated scapholunate relative motion over a full range of wrist positions, and found that there was a significant amount of variation in the location and orientation of the rotation axis between the two bones. Together the findings from the two studies illustrate the complexity and subject specificity of normal carpal mechanics, and should provide insights that can guide the development of anatomical wrist ligament repair surgeries that restore normal function.

The relationship between changes in cardiovascular function and changes in VO2peak following SIT

Background: It is well known that sprint interval training (SIT), induces significant increases in peak oxygen uptake (VO2peak) at the group level. However, there have been only a few studies that have addressed the variability of VO2peak response following SIT, and precise mechanism(s) that may explain individual magnitude of response are unknown. Purpose: Therefore, the purpose of this thesis was to: 1) examine the inter-individual variability of the VO2peak response following SIT, 2) to inspect the relationship between changes in both central and peripheral measures and changes in VO2peak, and 3) to assess if peripheral or central adaptations play a role in whether an individual is a high or low responder with respect to VO2peak. Subjects: Twenty-two young, recreationally active males (age: 20.4 1.7 years; weight: 78.4 10.2 kg; VO2peak: 3.7 0.62 L/min) Methods: VO2peak (L/min), peak cardiac output (Qpeak [L/min]), and peak deoxygenated hemoglobin (HHbpeak [mM]) were measured before and after 16 sessions of SIT (Tabata Protocol) over four weeks. Peak a-vO2diff was calculated using a derivation of the Fick equation. Results: Due to a systematic error, HHbpeak could not be used to differentiate between individual responses. There was a large range of VO2peak response from pre to post testing (-4.75 to 32.18% change) and there was a significant difference between the Low Response Group (LRG) (n=8) and the High Response Group (HRG) (n=8) [f(1, 14)= 64.27, p<0.001]. Furthermore, there was no correlation between delta () VO2peak and Qpeak (r=-0.18, p=0.46) for all participants, nor was there an interaction effect between the Low and High Response Groups [f(1,11)=0.572, p=0.47]. Lastly, there was a significant correlation between VO2peak and peak a-vO2diff [r=0.692, p<0.001], and a significant interaction effect with peak a-vO2diff [f(1, 14)= 13.27, p<0.004] when comparing the HRG to the LRG. Conclusions: There was inter-individual variability of VO2peak response following 4 weeks of SIT, but central adaptations did not influence this variation. This suggests that peripheral adaptations may be responsible for VO2peak adaptation.

Thirty minutes of handgrip exercise enhances brachial artery flow-mediated dilation in response to two different shear stress profiles.

The walls of blood vessels are lined with a single-cell layer of endothelial cells. As blood flows through the arteries, a frictional force known as shear stress is sensed by mechanosensitive structures on the endothelium. Short and long term changes in shear stress can have a significant influence on the regulation of endothelial function. Acutely, shear stress triggers a pathway that culminates in the release of vasodilatory molecules from the endothelium and subsequent vasodilation of the artery. This endothelial response is known as flow mediated dilation (FMD). FMD is used as an index of endothelial function and is commonly assessed using reactive hyperemia (RH)-FMD, a method which elicits a large, short lived increase in shear stress following the release of a brief (5 min) forearm occlusion. A recent study found that a short term exposure (30 min) to a sustained elevation in shear stress potentiates subsequent RH-FMD. FMD can also result from a more prolonged, sustained increase in shear stress elicited by handgrip exercise (HGEX-FMD). There is evidence to suggest that interventions and conditions impact FMD resulting from sustained and transient shear stress stimuli differently, indicating that HGEX-FMD and RH-FMD provide different information about endothelial function. It is unknown whether HGEX-FMD is improved by short term exposure to shear stress. Understanding how exercise induced FMD is regulated is important because it contributes to blood flow responses during exercise. The study purpose was therefore to assess the impact of a handgrip exercise (intervention) induced sustained elevation in shear stress on subsequent brachial artery (BA) HGEX-FMD. Twenty healthy male participants (22±3yrs) preformed a 30-minute HGEX intervention on two experimental days. BA-FMD was assessed using either an RH or HGEX shear stress stimulus at 3 time points: pre-intervention, 10 min post and 60 min post. FMD and shear stress magnitude were determined via ultrasound. Both HGEX and RH-FMD increased significantly from pre-intervention to 10 min-post (p<0.01). These findings indicate that FMD stimulated by exercise induced increases in shear stress is potentiated by short term shear stress exposure. These findings advance our understanding regarding the regulation of endothelial function by shear stress.