Gravitostat: A Homeostatic Regulator of Body Weight

Abstract

This project focuses on elucidating central and peripheral physiological mechanisms behind load-induced body weight reduction. These pre-clinical works are a continuation of previous studies in obese humans and Diet-Induced Obese (DIO) rodents, which demonstrated that increased weight load leads to a significant reduction in biological body weight and food intake. Based on these findings, our research group hypothesized that the observed body weight reduction is due to a homeostatic mechanism which we termed "the gravitostat." This mechanism is activated by increased load, which in turn is likely to stimulate weight sensors in the lower extremities. These are then likely to send signals to integrating centers in the brain to reduce appetite. This thesis encompasses mapping studies performed in the brain and spine of weight-bearing DIO mice to identify regions involved in load-induced weight loss, as well as an exploration of alternative methods for load application. Since load-induced weight loss is a relatively acute process, we additionally explored potential alterations in water balance and showed that water and sodium levels are unaffected in weight-bearing rats. This strengthened our previous findings that fat loss is the primary mechanism for body weight reduction in weight-bearing rodents. Finally, we developed a method which allows animals to recover from the surgical procedure used to increase load, by implanting a fillable capsule. This allowed us to fill capsules with wolfram granulate and increase the load once the rodent has recovered from the surgical trauma. We also utilized subcutaneous implantation of capsules on rodents’ back, which seems to induce less surgical trauma than intraperitoneal implantation. The main findings in this thesis include the identification of a group of neurons activated by increased load in the medial Nucleus of Solitary Tract (mNTS) and the dorsal horn (DH) of the Lumbar Spine (LS) in mice. More specifically, methods such as immunohistochemistry and RNAscope were employed for closer identification of load-activated neurons, such as Norepinephrine (NE) containing cells in the brainstem. The effects of capsaicin in the DH lead us to speculate that the nerves transmitting information from the hindlimbs contain TRPV1-channels. However, the identity of the cells receiving these projections remains to be identified. In conclusion, these findings have established a strong foundation for future studies to identify other potential regions involved in load-induced weight loss. Our results potentially pave the way for developing effective preventative measures for obesity, as well as pharmacological targeting of regions involved in this process. This research contributes to our understanding of body weight regulation mechanisms and may lead to novel approaches in obesity management.