The role of prokineticin 2 in energy homeostasis

Obesity is a growing public health problem as its prevalence continues to increase. The hypothalamus is a region of the brain important in regulating energy homeostasis via complex, interacting neuronal circuits and neuropeptides. The prokineticins are cysteine-rich secreted proteins involved in regulating a diverse range of physiological functions. Prokineticin 2 (PK2), a recently discovered 81 amino acid peptide, is highly expressed in the suprachiasmatic nucleus and prokineticin receptors are expressed in several hypothalamic regions involved in energy homeostasis. However, the role of PK2 in the regulation of food intake and body weight has not been investigated. The studies described in this thesis investigate the role of PK2 in energy homeostasis. Intracerebroventricular (ICV) administration of PK2 potently reduced food intake in rats. This effect was specific; ICV PK2 did not affect locomotor activity or behaviour nor did it alter energy expenditure. Immunoblockade of PK2 by ICV administration of anti-PK2 IgG resulted in an increase in food intake in satiated rats. Furthermore, fasting reduced hypothalamic PK2 mRNA expression by approximately 50% in 12- and 24- hour fasted rats. These results suggest that hypothalamic PK2 may have a physiological role in appetite regulation. ICV administration of PK2 in rats resulted in c-fos expression, suggesting neuronal activation, in the supraoptic nucleus, arcuate nucleus (ARC), paraventricular nucleus and anterior hypothalamic area. Direct injection of PK2 into these hypothalamic sites potently reduced food intake, suggesting that the anorexigenic effects of PK2 may be mediated via these hypothalamic areas. Hypothalamic explants treated with PK2 significantly increased a-melanocyte stimulating hormone (a-MSH) release. ICV coadministration of PK2 and agouti-related protein (AgRP) (a melanocortin receptor antagonist) attenuated the anorexigenic effect of PK2, suggesting that the ARC melanocortin system may mediate part of the anorexigenic effects of PK2. In accord with this, following central PK2 administration the majority (64%) of c-fos-expressing neurones in the ARC were pro-opiomelanocortin (ROMC)-expressing neurones. Chronic peripheral administration of PK2 in lean and obese mice significantly reduced food intake with no evidence of tachyphylaxis, resulting in a significant reduction in body weight in both types of mice. These studies have provided novel information about the effects and role of PK2 in energy homeostasis. I propose that endogenous PK2 may have a physiological role in appetite regulation and may be a new target for the development of anti obesity agents

Illusions of Self‐Motion during Magnetic Resonance ‐Guided Focused Ultrasound Thalamotomy for Tremor

© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Objective: Brain networks mediating vestibular perception of self‐motion overlap with those mediating balance. A systematic mapping of vestibular perceptual pathways in the thalamus may reveal new brain modulation targets for improving balance in neurological conditions. Methods: Here, we systematically report how magnetic resonance‐guided focused ultrasound surgery of the nucleus ventralis intermedius of the thalamus commonly evokes transient patient‐reported illusions of self‐motion. In 46 consecutive patients, we linked the descriptions of self‐motion to sonication power and 3‐dimensional (3D) coordinates of sonication targets. Target coordinates were normalized using a standard atlas, and a 3D model of the nucleus ventralis intermedius and adjacent structures was created to link sonication target to the illusion. Results: A total of 63% of patients reported illusions of self‐motion, which were more likely with increased sonication power and with targets located more inferiorly along the rostrocaudal axis. Higher power and more inferiorly targeted sonications increased the likelihood of experiencing illusions of self‐motion by 4 and 2 times, respectively (odds ratios = 4.03 for power, 2.098 for location). Interpretation: The phenomenon of magnetic vestibular stimulation is the most plausible explanation for these illusions of self‐motion. Temporary unilateral modulation of vestibular pathways (via magnetic resonance‐guided focused ultrasound) unveils the central adaptation to the magnetic field‐induced peripheral vestibular bias, leading to an explicable illusion of motion. Consequently, systematic mapping of vestibular perceptual pathways via magnetic resonance‐guided focused ultrasound may reveal new intracerebral targets for improving balance in neurological conditions. ANN NEUROL 2024Peer reviewe