Endocrinology - Papers

Using mouse models, the authors demonstrate that myostatin functions as an endocrine hormone that directly stimulates pituitary FSH synthesis, redefining the regulatory hierarchy for FSH beyond activins. This uncovers a skeletal muscle–pituitary endocrine axis and raises caution that myostatin antagonism to enhance muscle mass may adversely affect fertility.

This mechanistic study demonstrates that mammalian cells produce cyanide endogenously at low levels, where it functions as a gasotransmitter to enhance mitochondrial bioenergetics, metabolism, and proliferation, while higher concentrations are bioenergetically detrimental. Cyanide induces protein S-cyanylation and low-dose supplementation is cytoprotective in hypoxia/reoxygenation models; excessive production, as in nonketotic hyperglycinemia, is harmful.

This study uncovers a CYP51A1-driven pathway that converts an oxysterol to androgens, effectively bypassing CYP17A1. Screening of 57 human P450s and stable isotope tracing establish CYP51A1 as uniquely capable and essential for this bypass, providing a mechanism for persistent androgen biosynthesis during CYP17A1 inhibition in prostate cancer.

This study identifies a lysosomal lipolysis program in adipocytes that depends on LAL (LIPA) and MiT/TFE transcription factors and predominates during prolonged fasting, whereas canonical neutral lipases (e.g., ATGL) dominate acute adrenergic responses. The mechanism was demonstrated using pharmacologic and genetic perturbations in mice and in murine/human adipocyte and adipose explants.

This study presents a foundational spatio-cellular atlas of the human hypothalamus, delineating cell types and their spatial organization that underpin neuroendocrine control. The resource enables mechanistic interrogation of human hypothalamic circuits relevant to appetite, thermoregulation, reproduction, and pituitary axis regulation.

Adipose β-adrenergic stimulation (adrenaline/β3 agonist) and acute stress induce GDF15 secretion from white adipose tissue via lipolysis and M2-like macrophage activation. Anxiety-like behavior elicited by stress is abolished in GFRAL-deficient mice, establishing a peripheral endocrine GDF15→GFRAL axis linking metabolism to behavior.

This translational study shows that G6PC2 in pancreatic α cells determines the glucose set point for glucagon secretion. By linking genetic variation at G6PC2 to α-cell glucose sensing, it provides a mechanistic basis for hyperglucagonemia in type 2 diabetes and a potential therapeutic target.

Across three Chinese cohorts (n=226), the gut fungus Aspergillus tubingensis was enriched in PCOS and induced a PCOS-like phenotype upon colonization in mice by inhibiting AhR signaling and decreasing IL-22 in ILC3s. A strain-diversity metabolite screen identified AT-C1 as an endogenous AhR antagonist mediating the phenotype. This establishes a mycobiome-derived mechanism for PCOS and nominates AhR signaling restoration as a therapeutic strategy.

Minor intron splicing is broadly disrupted during MASH progression, causing Insig1/2 intron retention, SREBP1c activation, and a switch to IDH1-driven reductive carboxylation that fuels de novo lipogenesis and ammonia accumulation to initiate fibrosis. Ammonia clearance or IDH1 inhibition blocked fibrogenesis, and Zrsr1 overexpression rescued splicing defects and disease. These define a splicing-metabolism checkpoint as a therapeutic target in MASLD/MASH.

The study identifies a fasting-activated neuroimmune circuit in mice whereby catecholaminergic intestinal neurons drive β2-adrenergic receptor–dependent migration/accumulation of ILC2s to the pancreas to support glucagon secretion and gluconeogenesis. This establishes inter-organ neuronal control of immune cells that orchestrates pancreatic endocrine function and systemic glucose homeostasis.

Using multiple genetic mouse models, the authors show that mechanosensory Piezo2 in Runx3/PV sensory neurons constrains thermogenic adipose remodeling and systemic hypermetabolism. Piezo2 deletion protects against high-fat-diet obesity, improves insulin sensitivity, and induces browning/beiging, likely via increased norepinephrine.

This integrated genomics-to-phenotype study maps MCT8 variant classes to survival and 24/32 clinical features, identifies a mild phenocopy in population cohorts, delineates seven functional domains, and delivers a pathogenicity–severity classifier with AUC 0.91/0.86 for 8,151 variants. Therapeutic effectiveness did not differ across loss-of-function categories, informing counseling and trial design.

Across two human cohorts, Barnesiella intestinihominis was depleted in T2D. Oral live B. intestinihominis or its metabolite acetate improved hyperglycemia and hepatic metabolic dysfunction in HFD/STZ and db/db mice by increasing FGF21 via HDAC9 inhibition and H3K27 acetylation at the FGF21 promoter. The prebiotic puerarin promoted B. intestinihominis growth and replicated metabolic benefits.

The authors identify Raptin, a peptide hormone cleaved from RCN2, whose secretion peaks during sleep and is controlled by an SCN–PVN circuit. Raptin binds GRM3 in hypothalamic and gastric neurons to suppress appetite and slow gastric emptying via PI3K-AKT, protecting against obesity; human data link sleep deficiency with impaired Raptin and an RCN2 nonsense variant with night eating and obesity.

Using zonally targeted genetic disruption of hepatic insulin signaling, the authors show periportal insulin resistance increases gluconeogenesis but paradoxically reduces lipogenesis and steatosis, whereas pericentral insulin resistance lowers pericentral steatosis without impairing glucose control. A shift of glycolytic flux from liver to muscle contributes to preserved glucose homeostasis under pericentral insulin resistance.

In a mechanistic study, maternal circadian disruption during pregnancy programmed offspring toward obesity, with arrhythmic feeding, hypothalamic leptin resistance, and hepatic clock reprogramming. Aligning caloric restriction to the active phase in offspring nearly reversed the obese phenotype, highlighting a causal circadian programming of metabolic plasticity.

This study reveals an immune–adipose mechanism whereby neutrophils act within adipose tissue to preserve lipid storage when sympathetic stimulation would otherwise drive lipolysis. The work defines an immunometabolic brake on adrenergic lipolysis, highlighting bidirectional crosstalk between innate immunity and adipocyte energy handling.

This mechanistic study identifies Eepd1 as an adipose-enriched, myristoylation-dependent activator of PKA signaling that drives lipolysis and thermogenesis. Loss of Eepd1 impairs cold-induced energy expenditure, while pharmacologic restoration (retigabine dihydrochloride) mitigates obesity, highlighting Eepd1 as a therapeutic target.

In a retrospective cohort of 2,311 subclinical hypothyroidism patients, higher TSH levels correlated with greater AF prevalence. Complementary experiments showed TSH directly modulates cardiomyocyte ion channel expression and electrophysiology via TSHR/cAMP/PKA, increasing automaticity and altering action potentials.

This mechanistic study shows that lysosomal acid lipase-driven lipolysis is upregulated during fasting, cold exposure, and β-adrenergic stimulation, and is essential for maintaining circulating FFAs, thermogenesis, and energy expenditure. Adipocyte LIPA deficiency impairs cold tolerance and increases susceptibility to diet-induced obesity, acting independently of cytosolic ATGL.

Across 732,564 participants from 55 cohorts, genome-wide interaction meta-analyses identified 17 loci where genetic effects on lipids depend on short or long sleep. The results implicate vitamin D receptor–related signaling in sleep-associated lipid perturbations, suggesting new mechanistic targets for dyslipidemia among individuals with atypical sleep duration.

In mice, hypothalamic POMC satiety neurons paradoxically promote sugar appetite via a projection to the paraventricular thalamus that inhibits postsynaptic neurons through mu-opioid receptors. The circuit is preferentially engaged during sugar consumption in sated states, and its inhibition reduces high-sugar intake.

This study defines a gut–joint axis in which decreased GUDCA and intestinal FXR signaling modulate osteoarthritis via GLP-1. In mice, inhibiting intestinal FXR alleviated osteoarthritis through GLP-1, and GLP-1 receptor activation mitigated disease while blockade attenuated benefits. Human cohorts showed altered bile acid metabolism consistent with the mechanism.

This study introduces a selective small molecule (CCM) that binds the BMAL1 PASB domain to modulate BMAL1-CLOCK activity, shifting circadian oscillations and suppressing inflammatory/phagocytic pathways in macrophages. Structural and cellular data establish target engagement and functional consequences, opening a path to clock-directed immunometabolic therapeutics.