Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of hormones and neuropeptides. In this review, we examine the variability in the individual peptides produced in different tissues ...and the impact of the simultaneous presence of their precursors or fragments. We also discuss the problems inherent in accurately measuring which of the precursors and their derived peptides are present in biological samples. We address how not being able to measure all the combinations of precursors and fragments quantitatively has affected our understanding of the pathophysiology associated with POMC processing. To understand how different ratios of peptides arise, we describe the role of the pro-hormone convertases (PCs) and their tissue specificities and consider the cellular processing pathways which enable regulated secretion of different peptides that play crucial roles in integrating a range of vital physiological functions. In the pituitary, correct processing of POMC peptides is essential to maintain the hypothalamic-pituitary-adrenal axis, and this processing can be disrupted in POMC-expressing tumors. In hypothalamic neurons expressing POMC, abnormalities in processing critically impact on the regulation of appetite, energy homeostasis, and body composition. More work is needed to understand whether expression of the POMC gene in a tissue equates to release of bioactive peptides. We suggest that this comprehensive view of POMC processing, with a focus on gaining a better understanding of the combination of peptides produced and their relative bioactivity, is a necessity for all involved in studying this fascinating physiological regulatory phenomenon.
In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that ...cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.
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•IL-6 suppresses hepatic ketogenesis in pre-cachectic, tumor-bearing mice•During caloric deficiency, hypoketonemia triggers marked glucocorticoid secretion•Glucocorticoids, induced by metabolic stress, suppress intratumoral immunity•Stress-induced glucocorticoids cause failure of cancer immunotherapy
Flint and Janowitz et al. reveal the intricate links between cancer cachexia, hepatic metabolism, and tumor immunology. They find that tumor-induced IL-6 suppresses hepatic ketogenesis, and during caloric deficiency, this triggers marked glucocorticoid secretion. This hormonal stress response suppresses intratumoral immunity and causes failure of anti-cancer immunotherapy.
Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk
. More than 60% of this effect is attributable to the ability of ...metformin to lower body weight in a sustained manner
. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.
The oral cavity is exposed to the external environment and from a very young age is colonized by infectious agents. Under certain circumstances including poor oral hygiene, dry mouth, trauma, and the ...use of antibiotics, oral infections can occur. They can result in damage to the oral cavity including teeth and their support structures. Oral infections can also lead to the extension of infection into surrounding tissues and to systemic infections. Chronic oral infection is a recognized risk factor for heart disease. Older adults are at high risk for oral infections and associated complications. Tooth loss, for which infection is the most significant cause, leads to cosmetic changes and a decreased ability to masticate certain foods that can lead to malnutrition. Chronic oral infections and the manipulation of teeth and supporting structures can lead to the hematogenous spread of infection including the infection of artificial joints and endocardial implants. Good oral hygiene, the use of fluoride, regular dental care, and the appropriate use of antibiotics can all reduce oral infections and their associated complications. J Am Geriatr Soc 68:411–416, 2020
The fat mass and obesity-associated (FTO) gene was placed center stage when common intronic variants within the gene were robustly associated with human obesity. Murine models of perturbed Fto ...expression have shown effects on body weight and composition. However, a clear understanding of the link between FTO intronic variants and FTO activity has remained elusive. Two recent reports now indicate that obesity-associated SNPs appear functionally connected not with FTO but with two neighboring genes: IRX3 and RPGRIP1L. Here, we review these new findings and consider the implications for future analysis of GWAS hits.
Tung et al. review how common SNPs in the fat mass and obesity-associated (FTO) gene have been linked to human obesity by GWAS and discuss recent work suggesting that flanking genes, including IRX3 and RPGRIP1L, may also be important regulators of body weight.
The Hormonal Control of Food Intake Coll, Anthony P.; Farooqi, I. Sadaf; O'Rahilly, Stephen
Cell,
04/2007, Letnik:
129, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Numerous circulating peptides and steroids produced in the body influence appetite through their actions on the hypothalamus, the brain stem, and the autonomic nervous system. These hormones come ...from three major sites—fat cells, the gastrointestinal tract, and the pancreas. In this Review we provide a synthesis of recent evidence concerning the actions of these hormones on food intake.
The Sample Analysis at Mars (SAM) instrument on board the Mars Science Laboratory Curiosity rover is designed to conduct inorganic and organic chemical analyses of the atmosphere and the surface ...regolith and rocks to help evaluate the past and present habitability potential of Mars at Gale Crater. Central to this task is the development of an inventory of any organic molecules present to elucidate processes associated with their origin, diagenesis, concentration, and long‐term preservation. This will guide the future search for biosignatures. Here we report the definitive identification of chlorobenzene (150–300 parts per billion by weight (ppbw)) and C2 to C4 dichloroalkanes (up to 70 ppbw) with the SAM gas chromatograph mass spectrometer (GCMS) and detection of chlorobenzene in the direct evolved gas analysis (EGA) mode, in multiple portions of the fines from the Cumberland drill hole in the Sheepbed mudstone at Yellowknife Bay. When combined with GCMS and EGA data from multiple scooped and drilled samples, blank runs, and supporting laboratory analog studies, the elevated levels of chlorobenzene and the dichloroalkanes cannot be solely explained by instrument background sources known to be present in SAM. We conclude that these chlorinated hydrocarbons are the reaction products of Martian chlorine and organic carbon derived from Martian sources (e.g., igneous, hydrothermal, atmospheric, or biological) or exogenous sources such as meteorites, comets, or interplanetary dust particles.
Key Points
First in situ evidence of nonterrestrial organics in Martian surface sediments
Chlorinated hydrocarbons identified in the Sheepbed mudstone by SAM
Organics preserved in sample exposed to ionizing radiation and oxidative condition
Sequence variants in the first intron of FTO are strongly associated with human obesity and human carriers of the risk alleles show evidence for increased appetite and food intake. Mice globally ...lacking Fto display a complex phenotype characterised by both increased energy expenditure and increased food intake. The site of action of FTO on energy balance is unclear. Fasting reduces levels of Fto mRNA in the arcuate nucleus (ARC) of the hypothalamus, a site where Fto expression is particularly high. In this study, we have extended this nutritional link by demonstrating that consumption of a high fat diet (45%) results in a 2.5 fold increase in Arc Fto expression. We have further explored the role of hypothalamic Fto in the control of food intake by using stereotactic injections coupled with AAV technology to bi-directionally modulate Fto expression. An over expression of Fto protein by 2.5-fold in the ARC results in a 14% decrease in average daily food intake in the first week. In contrast, knocking down Arc Fto expression by 40% increases food intake by 16%. mRNA levels of Agrp, Pomc and Npy, ARC-expressed genes classically associated with the control of food intake, were not affected by the manipulation of Fto expression. However, over expression of Fto resulted in a 4-fold increase in the mRNA levels of Stat3, a signalling molecule critical for leptin receptor signalling, suggesting a possible candidate for the mediation of Fto's actions. These data provide further support for the notion that FTO itself can influence key components of energy balance, and is therefore a strong candidate for the mediation of the robust association between FTO intronic variants and adiposity. Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man.
The strongest BMI-associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression ...studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake.
In July 2015, the Journal of the American Geriatrics Society published a manuscript titled, “Failing to Focus on Healthy Aging: A Frailty of Our Discipline?” In response, the American Geriatrics ...Society (AGS) Clinical Practice and Models of Care Committee and Public Education Committee developed a white paper calling on the AGS and its members to play a more active role in promoting healthy aging. The executive summary presented here summarizes the recommendations from that white paper. The full version is published online at GeriatricsCareOnline.org. Life expectancy has increased dramatically over the last century. Longer life provides opportunity for personal fulfillment and contributions to community but is often associated with illness, discomfort, disability, and dependency at the end of life. Geriatrics has focused on optimizing function and quality of life as we age and reducing morbidity and frailty, but there is evidence of earlier onset of chronic disease that is likely to affect the health of future generations of older adults. The AGS is committed to promoting the health, independence, and engagement of all older adults as they age. Geriatrics as an interprofessional specialty is well positioned to promote healthy aging. We draw from decades of accumulated knowledge, skills, and experience in areas that are central to geriatric medicine, including expertise in complexity and the biopsychosocial model; attention to function and quality of life; the ability to provide culturally competent, person‐centered care; the ability to assess people's preferences and values; and understanding the importance of systems in optimizing outcomes. J Am Geriatr Soc 67:17–20, 2019.
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