20 results found
Yang L, Demetriou L, Wall M, et al., 2020, Kisspeptin enhances brain responses to olfactory and visual cues of attraction in men, JCI insight, Vol: 5, ISSN: 2379-3708
Successful reproduction is a fundamental physiological process which relies on the integration of sensory cues of attraction with appropriate emotions and behaviors and the reproductive axis. However, the factors responsible for this integration remain largely unexplored. Using functional neuroimaging, hormonal and psychometric analyses, we demonstrate that the reproductive hormone kisspeptin enhances brain activity in response to olfactory and visual cues of attraction in men. Furthermore, the brain regions enhanced by kisspeptin correspond to areas within the olfactory and limbic systems that govern sexual behavior and perception of beauty as well as overlapping with its endogenous expression pattern. Of key functional and behavioral significance, we observed that kisspeptin was most effective in men with lower sexual quality of life scores. As such, our results reveal a previously undescribed attraction pathway in humans activated by kisspeptin, and identify kisspeptin signaling as a new therapeutic target for related reproductive and psychosexual disorders.
Fernandes-Freitas I, Milona A, Murphy KG, et al., 2020, Live birth in sex-reversed XY mice lacking the nuclear receptor Dax1, Scientific Reports, Vol: 10, ISSN: 2045-2322
The nuclear hormone receptor Dax1 functions during development as a testes-determining gene. However, the phenotype of male mice lacking Dax1 is strain-dependent due to the background-specific abundance of male-determining Sry gene-transcripts. We hypothesised that inter-individual variation in Sry mRNA-abundance would result in a spectrum of phenotypes even within-strain. We found that while all XY C57BL/6J mice lacking Dax1 presented as phenotypic females, there was a marked inter-individual variability in measures of fertility. Indeed, we report rare occasions where sex-reversed mice had measures of fertility comparable to those in control females. On two occasions, these sex-reversed XY mice were able to give birth to live offspring following mating to stud-males. As such, this work documents within-strain variability in phenotypes of XY mice lacking Dax1, and reports for the first time a complete sex-reversal capable of achieving live birth in these mice.
Milona A, Massafra V, Vos H, et al., 2019, Steroidogenic control of liver metabolism through a nuclear receptor-network, Molecular Metabolism, Vol: 30, Pages: 221-229, ISSN: 2212-8778
OBJECTIVE: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown. METHODS AND RESULTS: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1. CONCLUSIONS: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.
Jones B, Buenaventura T, Kanda N, et al., 2018, Targeting GLP-1 receptor trafficking to improve agonist efficacy, Nature Communications, Vol: 9, ISSN: 2041-1723
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a novel series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.
Owen BM, Sondhi V, Liu J, et al., 2016, Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in Leydig cells, Molecular Endocrinology, Vol: 30, Pages: 469-478, ISSN: 1944-9917
Androgen and estrogen biosynthesis in mammals requires the 17,20-lyase activity of cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase). Maximal 17,20-lyase activity in vitro requires the presence of cytochrome b5 (b5), and rare cases of b5 deficiency in human beings causes isolated 17,20-lyase deficiency. To study the consequences of conditional b5 removal from testicular Leydig cells in an animal model, we generated Cyb5(flox/flox):Sf1-Cre (LeyKO) mice. The LeyKO male mice had normal body weights, testis and sex organ weights, and fertility compared with littermates. Basal serum and urine steroid profiles of LeyKO males were not significantly different than littermates. In contrast, marked 17-hydroxyprogesterone accumulation (100-fold basal) and reduced testosterone synthesis (27% of littermates) were observed after human chorionic gonadotropin stimulation in LeyKO animals. Testis homogenates from LeyKO mice showed reduced 17,20-lyase activity and a 3-fold increased 17-hydroxylase to 17,20-lyase activity ratio, which were restored to normal upon addition of recombinant b5. We conclude that Leydig cell b5 is required for maximal androgen synthesis and to prevent 17-hydroxyprogesterone accumulation in the mouse testis; however, the b5-independent 17,20-lyase activity of mouse steroid 17-hydroxylase/17,20-lyase is sufficient for normal male genital development and fertility. LeyKO male mice are a good model for the biochemistry but not the physiology of isolated 17,20-lyase deficiency in human beings.
Talukdar S, Zhou Y, Li D, et al., 2016, A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and Type 2 diabetic subjects, Cell Metabolism, Vol: 23, Pages: 427-440, ISSN: 1550-4131
FGF21 plays a central role in energy, lipid, and glucose homeostasis. To characterize the pharmacologic effects of FGF21, we administered a long-acting FGF21 analog, PF-05231023, to obese cynomolgus monkeys. PF-05231023 caused a marked decrease in food intake that led to reduced body weight. To assess the effects of PF-05231023 in humans, we conducted a placebo-controlled, multiple ascending-dose study in overweight/obese subjects with type 2 diabetes. PF-05231023 treatment resulted in a significant decrease in body weight, improved plasma lipoprotein profile, and increased adiponectin levels. Importantly, there were no significant effects of PF-05231023 on glycemic control. PF-05231023 treatment led to dose-dependent changes in multiple markers of bone formation and resorption and elevated insulin-like growth factor 1. The favorable effects of PF-05231023 on body weight support further evaluation of this molecule for the treatment of obesity. Longer studies are needed to assess potential direct effects of FGF21 on bone in humans.
Fibroblast growth factor 21 (FGF21) is a hormone induced by various metabolic stresses, including ketogenic and high-carbohydrate diets, that regulates energy homeostasis. In humans, SNPs in and around the FGF21 gene have been associated with macronutrient preference, including carbohydrate, fat, and protein intake. Here we show that FGF21 administration markedly reduces sweet and alcohol preference in mice and sweet preference in cynomolgus monkeys. In mice, these effects require the FGF21 co-receptor β-Klotho in the central nervous system and correlate with reductions in dopamine concentrations in the nucleus accumbens. Since analogs of FGF21 are currently undergoing clinical evaluation for the treatment of obesity and type 2 diabetes, our findings raise the possibility that FGF21 administration could affect nutrient preference and other reward behaviors in humans.
Fernandes-Freitas I, Owen BM, 2015, Metabolic roles of endocrine fibroblast growth factors, Current Opinion in Pharmacology, Vol: 25, Pages: 30-35, ISSN: 1471-4892
Considerable effort is currently being devoted to understanding the physiological and pharmacological action of the endocrine fibroblast growth factors (FGFs). These three proteins (FGF15/19, FGF21 and FGF23) act in a tissue-specific manner through a membrane-complex consisting of an FGF-receptor and α/βKlotho. FGF15/19 is produced in the intestine and regulates postprandial liver metabolism and gallbladder filling. FGF21 is largely liver-derived and co-ordinates adaptive changes in response to nutritional and physiological stresses. FGF23 signals from the bone to the kidney to maintain phosphate homeostasis. In pharmacological settings, FGF15/19, FGF21, and the prototypical FGF1, potentially represent novel treatments for obesity and diabetes. This review summarises the recent advances in our understanding of the biology of these important metabolic regulators.
Patel R, Bookout AL, Magomedova L, et al., 2015, Glucocorticoids Regulate the Metabolic Hormone FGF21 in a Feed-Forward Loop, MOLECULAR ENDOCRINOLOGY, Vol: 29, Pages: 213-223, ISSN: 0888-8809
Owen BM, Mangelsdorf DJ, Kliewer SA, 2015, Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21, TRENDS IN ENDOCRINOLOGY AND METABOLISM, Vol: 26, Pages: 22-29, ISSN: 1043-2760
Owen BM, Ding X, Morgan DA, et al., 2014, FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss, Cell Metabolism, Vol: 20, Pages: 670-677, ISSN: 1550-4131
The mechanism by which pharmacologic administration of the hormone FGF21 increases energy expenditure to cause weight loss in obese animals is unknown. Here we report that FGF21 acts centrally to exert its effects on energy expenditure and body weight in obese mice. Using tissue-specific knockout mice, we show that βKlotho, the obligate coreceptor for FGF21, is required in the nervous system for these effects. FGF21 stimulates sympathetic nerve activity to brown adipose tissue through a mechanism that depends on the neuropeptide corticotropin-releasing factor. Our findings provide an unexpected mechanistic explanation for the strong pharmacologic effects of FGF21 on energy expenditure and weight loss in obese animals.
Owen BM, Bookout AL, Ding X, et al., 2013, FGF21 contributes to neuroendocrine control of female reproduction, NATURE MEDICINE, Vol: 19, Pages: 1153-1156, ISSN: 1078-8956
Bookout AL, de Groot MHM, Owen BM, et al., 2013, FGF21 regulates metabolism and circadian behavior by acting on the nervous system, NATURE MEDICINE, Vol: 19, Pages: 1147-1152, ISSN: 1078-8956
Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth1; however, the site of action of these diverse effects remains unclear. FGF21 signals through a heteromeric cell-surface receptor composed of one of three FGF receptors (FGFR1c, FGFR2c or FGFR3c) in complex with β-Klotho2,3,4, a single-pass transmembrane protein that is enriched in metabolic tissues5. Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity and alters circadian behavior, which are all features of the adaptive starvation response. These effects are mediated through β-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding β-Klotho (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin and growth. These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21.
Papacleovoulou G, Abu-Hayyeh S, Nikolopoulou E, et al., 2013, Maternal cholestasis during pregnancy programs metabolic disease in offspring, JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 3172-3181, ISSN: 0021-9738
Atkin SD, Owen BM, Bookout AL, et al., 2013, Nuclear Receptor LRH-1 Induces the Reproductive Neuropeptide Kisspeptin in the Hypothalamus, MOLECULAR ENDOCRINOLOGY, Vol: 27, Pages: 598-605, ISSN: 0888-8809
Ding X, Boney-Montoya J, Owen BM, et al., 2012, beta Klotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism, CELL METABOLISM, Vol: 16, Pages: 387-393, ISSN: 1550-4131
Milona A, Owen BM, Cobbold JFL, et al., 2010, Raised Hepatic: Bile Acid Concentrations During Pregnancy in Mice Are Associated with Reduced Farnesoid X Receptor Function, HEPATOLOGY, Vol: 52, Pages: 1341-1349, ISSN: 0270-9139
Milona A, Owen BM, van Mil S, et al., 2010, The normal mechanisms of pregnancy-induced liver growth are not maintained in mice lacking the bile acid sensor Fxr, AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, Vol: 298, Pages: G151-G158, ISSN: 0193-1857
Owen BM, Milona A, van Mil S, et al., 2010, Intestinal Detoxification Limits the Activation of Hepatic Pregnane X Receptor by Lithocholic Acid, DRUG METABOLISM AND DISPOSITION, Vol: 38, Pages: 143-149, ISSN: 0090-9556
Owen BM, Van Mil SWC, Boudjelal M, et al., 2008, Sequencing and functional assessment of hPXR (NR1I2) variants in intrahepatic cholestasis of pregnancy, XENOBIOTICA, Vol: 38, Pages: 1289-1297, ISSN: 0049-8254
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