Biology subjects

Hill, J. W.

Publications and source records attributed to Hill, J. W..

4 recordsLinked to original sources

bioRxiv2024

IGF-1 and insulin receptors in LepRb neurons jointly regulate body growth, bone mass, reproduction, and metabolism

Leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, but whether these functions are mediated via insulin-like growth factor 1 receptor (IGF1R) signaling is unknown. IGF-1 and insulin can bind to each others receptors, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and simultaneously lacking IGF1R and insulin receptor (IR) in LepRb neurons (IGF1R/IRLepRb mice) and then characterized their body growth, bone morphology, reproductive and metabolic functions. We found that IGF1R and IR in LepRb neurons were required for normal timing of pubertal onset, while IGF1R in LepRb neurons played a predominant role in regulating adult fertility and exerted protective effects against reproductive aging. Accompanying these reproductive deficits, IGF1RLepRb mice and IGF1R/IRLepRb mice had transient growth retardation. Notably, IGF1R in LepRb neurons was indispensable for normal trabecular and cortical bone mass accrual in both sexes. These findings suggest that IGF1R in LepRb neurons is involved in the interaction among body growth, bone development, and reproduction. Though only mild changes in body weight were detected, simultaneous deletion of IGF1R and IR in LepRb neurons caused dramatically increased fat mass composition, decreased lean mass composition, lower energy expenditure, and locomotor activity in both sexes. Male IGF1R/IRLepRb mice exhibited impaired insulin sensitivity. These findings suggest that IGF1R and IR in LepRb neurons jointly regulated body composition, energy balance, and glucose homeostasis. Taken together, our studies identified the sex-dependent complex roles of IGF1R and IR in LepRb neurons in regulating body growth, reproduction, and metabolism.

neuroscience↗

bioRxiv2024

IGF-1 Acts through Kiss1-expressing Cells to Influence Metabolism and Reproduction

ObjectiveKisspeptin, encoded by the Kiss1 gene, ties puberty and fertility to energy status; however, the metabolic factors that control Kiss1-expressing cells need to be clarified. MethodsTo evaluate the impact of IGF-1 on the metabolic and reproductive functions of kisspeptin producing cells, we created mice with IGF-1 receptor deletion driven by the Kiss1 promoter (IGF1RKiss1 mice). Previous studies have shown IGF-1 and insulin can bind to each others receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we also generated mice with simultaneous deletion of the IGF1R and insulin receptor (IR) in Kiss1-expressing cells (IGF1R/IRKiss1 mice). ResultsLoss of IGF1R in Kiss1 cells caused stunted body length. In addition, female IGF1RKiss1 mice displayed lower body weight and food intake plus higher energy expenditure and physical activity. This phenotype was linked to higher proopiomelanocortin (POMC) expression and heightened brown adipose tissue (BAT) thermogenesis. Male IGF1RKiss1 mice had mild changes in metabolic functions. Moreover, IGF1RKiss1 mice of both sexes experienced delayed puberty. Notably, male IGF1RKiss1 mice had impaired adulthood fertility accompanied by lower gonadotropin and testosterone levels. Thus, IGF1R in Kiss1-expressing cells impacts metabolism and reproduction in a sex-specific manner. IGF1R/IRKiss1 mice had higher fat mass and glucose intolerance, suggesting IGF1R and IR in Kiss1-expressing cells together regulate body composition and glucose homeostasis. ConclusionsOverall, our study shows that IGF1R and IR in Kiss1 have cooperative roles in body length, metabolism, and reproduction.

neuroscience↗

bioRxiv2021

Spexin modulates molecular thermogenic profile of adipose tissue and thermoregulatory behaviors

Thermoregulation is a physiological process by which a mammal regulates body temperature in response to its environment. Within the human body, thermoregulatory behaviors and metabolism are modulated by circulating metabolic factors. In our study, we tested the ability of the neuropeptide spexin, which shares sequence homology to galanin, to regulate these functions in female mice. Supraphysiological levels of spexin in C57BL/6 mice were insufficient to protect against diet-induced obesity after 50 days of treatment. Behavioral analysis of long-term spexin treatment appeared to modulate anxiety-like behaviors by promoting exploratory behaviors and thermoregulatory behaviors of nest building that ceased when animals were housed at thermoneutral temperatures. Upon examination of the molecular profile of brown and white adipose tissue, treatment disrupted the thermogenic profile of white adipose tissue, in which {beta}3-adrenergic receptor expression was downregulated. Our results reveal novel functions for spexin as a modulator of thermoregulatory behaviors and adipose tissue metabolism. HighlightsO_LISpexin treatment did not protect against diet-induced obesity in female mice. C_LIO_LISpexin-treatment promoted thermoregulatory behaviors of nest building. C_LIO_LIBehaviors normalized when animals were housed in thermoneutral temperatures. C_LI Funding SourcesNot applicable Disclosure SummaryNothing to disclose

molecular biology↗

bioRxiv2021

Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells

BackgroundInterferon (IFN) pathway activation in tumors can have dual, sometimes opposing, influences on immune responses. Therapeutic inhibition of programmed cell death ligand (PD-L1) - a treatment that reverses PD-1-mediated suppression of tumor-killing T-cells - is linked to alterations in IFN signaling; however, less is known about the role of IFNs after treatment resistance. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined the consequences of PD-L1 blockade on IFN-related secretory changes in preclinical models of acquired resistance. MethodsTherapy-resistant cell variants were derived from orthotopically grown mouse tumors initially sensitive or insensitive to PD-L1 antibody treatment. Cells representing acquired resistance were analyzed for changes to IFN-regulated secretory machinery that could impact tumor progression. ResultsWe identified a PD-L1 treatment-induced secretome (PTIS) that was enriched for several IFN-stimulated genes (ISGs) and significantly enhanced when stimulated by type I IFNs (IFN or IFN{beta}). Secretory changes were specific to treatment-sensitive tumor models and found to suppress activation of T cells ex vivo while diminishing tumor cell cytotoxicity, revealing a tumor-intrinsic treatment adaptation with potentially broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth was slowed by the blockade of individual secreted PTIS components (such as IL6) and stopped altogether by a more generalized disruption of type I IFN signaling. In vitro, genetic or therapeutic methods to target PD-L1 could only partially recapitulate the IFN-enhanced PTIS phenotype, showing that in vivo-based systems with intact tumor:immune cell interactions are needed to faithfully mimic acquired resistance as it occurs in patients. ConclusionsThese results suggest that prolonged in vivo PD-L1 inhibition can rewire type I IFN signaling to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.

cancer biology↗