Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency DOI Creative Commons
Yijun Gui, Naima S. Dahir,

Yanan Wu

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(10), P. 113188 - 113188

Published: Oct. 1, 2023

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. However, MC3R knockout (KO) mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that KO activation AgRP neurons in response fasting, cold exposure, or ghrelin while exhibiting normal inhibition by sensory detection food ad libitum-fed state. Using conditional model, show control neuron fasting requires specific presence within Thus, crucial player responsiveness soma both hormonal neuronal signals energy need.

Language: Английский

Cachexia: A systemic consequence of progressive, unresolved disease DOI Creative Commons
Miriam Ferrer, Tracy G. Anthony, Janelle S. Ayres

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(9), P. 1824 - 1845

Published: April 1, 2023

Language: Английский

Citations

100
Significant sparse polygenic risk scores across 813 traits in UK Biobank DOI Creative Commons
Yosuke Tanigawa,

Junyang Qian,

Guhan Venkataraman

et al.

PLoS Genetics, Journal Year: 2022, Volume and Issue: 18(3), P. e1010105 - e1010105

Published: March 24, 2022

We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,500 traits using genetic and phenotype data in the UK Biobank. report 813 sparse PRS models with significant (p < 2.5 x 10 −5 ) incremental predictive performance when compared against covariate-only model that considers age, sex, types genotyping arrays, principal component loadings genotypes. correlation between number variants selected (Spearman’s ⍴ = 0.61, p 2.2 −59 for quantitative traits, 0.21, 9.6 −4 binary traits). The trained on European individuals showed limited transferability evaluated non-European provide weights Global Biobank Engine ( https://biobankengine.stanford.edu/prs ).

Language: Английский

Citations

80
Understanding the genetic complexity of puberty timing across the allele frequency spectrum DOI Creative Commons
Katherine A. Kentistou, Lena R Kaisinger, Stasa Stankovic

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(7), P. 1397 - 1411

Published: July 1, 2024

Abstract Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women the top bottom 1% polygenic risk exhibited ~11 ~14-fold higher risks delayed precocious puberty, respectively. identified several genes harboring rare loss-of-function variants ~200,000 including ZNF483 , which abolished impact risk. Variant-to-gene mapping approaches mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, uncharacterized G-protein-coupled receptor, GPR83 amplified signaling MC3R a key nutritional sensor. Shared menopause involved DNA damage response suggest that ovarian reserve might signal centrally to trigger puberty. also highlight body size-dependent mechanisms potentially link reproductive life disease.

Language: Английский

Citations

18
A comprehensive spatio-cellular map of the human hypothalamus DOI Creative Commons
John A. Tadross, Lukas Steuernagel, Georgina K.C. Dowsett

et al.

Nature, Journal Year: 2025, Volume and Issue: 639(8055), P. 708 - 716

Published: Feb. 5, 2025

Abstract The hypothalamus is a brain region that plays key role in coordinating fundamental biological functions 1 . However, our understanding of the underlying cellular components and neurocircuitries have, until recently, emerged primarily from rodent studies 2,3 Here we combine single-nucleus sequencing 433,369 human hypothalamic cells with spatial transcriptomics, generating comprehensive spatio-cellular transcriptional map hypothalamus, ‘HYPOMAP’. Although conservation neuronal cell types between humans mice, as based on transcriptomic identity, generally high, there are notable exceptions. Specifically, significant disparities identity pro-opiomelanocortin neurons expression levels G-protein-coupled receptors two species carry direct implications for currently approved obesity treatments. Out 452 types, find 291 clusters significantly enriched body mass index (BMI) genome-wide association study genes. This enrichment driven by 426 ‘effector’ Rare deleterious variants six these ( MC4R , PCSK1 POMC CALCR BSN CORO1A ) associate BMI at population level, has not been linked previously to BMI. Thus, HYPOMAP provides detailed atlas context serves an important resource identify new druggable targets treating wide range conditions, including reproductive, circadian metabolic disorders.

Language: Английский

Citations

8
Kisspeptins and the neuroendocrine control of reproduction: Recent progress and new frontiers in kisspeptin research DOI Creative Commons
Verónica Sobrino, María Soledad Avendaño,

Cecilia Perdices-López

et al.

Frontiers in Neuroendocrinology, Journal Year: 2022, Volume and Issue: 65, P. 100977 - 100977

Published: Jan. 7, 2022

In late 2003, a major breakthrough in our understanding of the mechanisms that govern reproduction occurred with identification reproductive roles kisspeptins, encoded by Kiss1 gene, and their receptor, Gpr54 (aka, Kiss1R). The discovery this unsuspected facet attracted an extraordinary interest boosted intense research activity, human model species, that, relatively short period, established series basic concepts on physiological kisspeptins. Such fundamental knowledge, gathered these early years kisspeptin research, set scene for more recent in-depth dissection intimacies neuronal networks involving neurons, precise regulation molecular underpinnings function kisspeptins as pivotal regulators all key aspects function, from puberty onset to pulsatile gonadotropin secretion metabolic control fertility. While no clear temporal boundaries between two periods can be defined, review we will summarize most prominent advances last ten years, means provide up-dated view state art potential paths future progress dynamic, ever growing domain Neuroendocrinology.

Language: Английский

Citations

58
Molecular basis of normal and pathological puberty: from basic mechanisms to clinical implications DOI
Jesús Argente, Leo Dunkel, Ursula B. Kaiser

et al.

The Lancet Diabetes & Endocrinology, Journal Year: 2023, Volume and Issue: 11(3), P. 203 - 216

Published: Jan. 5, 2023

Language: Английский

Citations

41
Targeting the central melanocortin system for the treatment of metabolic disorders DOI
Patrick Sweeney, Luis E. Gimenez, Ciria C. Hernández

et al.

Nature Reviews Endocrinology, Journal Year: 2023, Volume and Issue: 19(9), P. 507 - 519

Published: June 26, 2023

Language: Английский

Citations

32
Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity DOI Creative Commons
Lena R Kaisinger, Katherine A. Kentistou, Stasa Stankovic

et al.

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(8), P. 100362 - 100362

Published: Aug. 1, 2023

Obesity contributes substantially to the global burden of disease and has a significant heritable component. Recent large-scale exome sequencing studies identified several genes in which rare, protein-coding variants have large effects on adult body mass index (BMI). Here we extended such work by performing sex-stratified associations UK Biobank study (N∼420,000). We rare heterozygous loss-of-function increases BMI women (DIDO1, PTPRG, SLC12A5) men (SLTM), with effect sizes up ∼8 kg/m2. This is complemented analyses implicating OBSCN MADD for recalled childhood adiposity. The known functions these genes, as well findings common variant genome-wide pathway enrichment analyses, suggest role neuron death, apoptosis, DNA damage response mechanisms susceptibility obesity across life-course. These highlight importance considering sex-specific life-course genetic regulation obesity.

Language: Английский

Citations

28
Pumping the Brakes on Psychosocial Acceleration Theory: Revisiting its underlying assumptions DOI Creative Commons
Anthony A. Volk

Evolution and Human Behavior, Journal Year: 2025, Volume and Issue: 46(1), P. 106657 - 106657

Published: Jan. 1, 2025

Language: Английский

Citations

1
Melanocortin 3 receptor regulates hepatic autophagy and systemic adiposity DOI Creative Commons
Tushar Patel,

Joo Yun Jun,

Arnold Y. Seo

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 16, 2025

Abstract Systemic lipid homeostasis requires hepatic autophagy, a major cellular program for intracellular fat recycling. Here, we find melanocortin 3 receptor (MC3R) regulates autophagy in addition to its previously established CNS role systemic energy partitioning and puberty. Mice with Mc3r deficiency develop obesity triglyceride accumulation disrupted hepatocellular autophagosome turnover. partially inactive human MC3R due obesogenic variants demonstrate similar autophagic dysfunction. In vitro vivo activation of upregulates through LC3II activation, TFEB cytoplasmic-to-nuclear translocation, subsequent downstream gene activation. MC3R-deficient hepatocytes had blunted autophagosome-lysosome docking droplet clearance. Finally, the liver-specific rescue was sufficient restore improve hepatocyte mitochondrial function expenditures, reduce adipose tissue accumulation, body weight both male female mice. We thus report regulating adiposity.

Language: Английский

Citations

1