David J Mangelsdorf was a senior colleague in the field of nuclear receptors who passed away unexpectedly in 2025. Dr Mangelsdorf and I share the same postdoctoral mentor at the Salk Institute. This article reflects on my scientific interaction with Dr Mangelsdorf, including the details of our research collaborations and how his discovery and early characterization of retinoid X receptor (RXR) and liver X receptor (LXR) receptor positively influence the research in my laboratory and many other laboratories in the nuclear receptor field.

Dr. David J. "Davo" Mangelsdorf is widely recognized for pioneering discoveries that transformed our understanding of nuclear receptor biology and endocrine physiology. Equally important, though less often described, was his extraordinary generosity as a mentor, collaborator, and scientific leader. This commentary reflects on his profound influence on my scientific development during my postdoctoral training at the University of Texas Southwestern Medical Center. As the scientific community reflects on Davo's remarkable career following his untimely passing in 2025, this personal perspective honors a legacy defined not only by his scientific discoveries, but also by the generations of scientists he inspired and empowered.

Diabetes results from an inflammatory insult to the pancreas. NFκB is a key transcription factor regulating cellular inflammatory responses. Therefore, we hypothesized that inflammatory exposures would acutely activate NFκB in the adult mouse pancreas and in isolated islets, leading to upregulation of target genes associated with inflammation and apoptosis. Mice were exposed to lipopolysaccharide (LPS) and isolated islets were exposed to a cytokine mixture to model a strong pro-inflammatory challenge. NFκB activation was determined by phosphorylation and nuclear translocation of NFκB proteins p65 and p50, dynamics of the inhibitors, IκBα and IκBβ, and the expression of NFκB target genes. NFκB target gene transcription was then correlated with p65 binding at promoter regions. Targeted apoptotic transcriptome changes were also evaluated. Systemic LPS exposure induced pancreatic NFκB activation, as evidenced by IκB oscillations and nuclear translocation of NFκB subunits. In isolated islets, cytokines triggered rapid p65 phosphorylation and DNA binding and increased NFκB target gene expression, with corresponding increases in specific promoter binding. Notably, anti-apoptotic genes were upregulated. These findings demonstrate that acute inflammatory stress activates NFκB in pancreatic tissue and islets, promoting a pro-inflammatory yet anti-apoptotic transcriptional response. Targeting NFκB at specific timepoints after inflammation may help prevent β-cell injury and diabetes development.

Obesity and diabetes arise from disrupted energy homeostasis, underscoring the need to identify mechanisms that enhance energy expenditure. Brown adipose tissue dissipates energy through mitochondria-dependent non-shivering thermogenesis; however, the transcriptional regulators coordinating this process remain incompletely defined. Here, we investigated the role of activating transcription factor 5 in thermogenic programming and mitochondrial metabolism in brown adipocytes using in vivo and in vitro models. Cold exposure and β3-adrenergic stimulation induced activating transcription factor 5 expression in brown adipose tissue and differentiated adipocytes, accompanied by activation of thermogenic gene programs. Mechanistically, activating transcription factor 5 functioned downstream of a nuclear protein kinase A-extracellular signal-regulated kinase pathway, whose nuclear activation was required for its induction and for upregulation of uncoupling protein 1. Loss of activating transcription factor 5 impaired thermogenic gene expression, reduced mitochondrial stress response and lipolytic programs, diminished mitochondrial oxidative capacity, and suppressed fatty acid oxidation, including reduced incorporation of fatty acid-derived carbons into the tricarboxylic acid cycle. Transcriptomic analysis revealed coordinated repression of pathways related to fatty acid oxidation, oxidative phosphorylation, and thermogenesis in activating transcription factor 5-deficient adipocytes. Live-cell imaging further confirmed that β3-adrenergic stimulation selectively enhanced nuclear kinase activity, establishing a nuclear-localized signaling axis. Together, these findings identify activating transcription factor 5 as a key transcriptional regulator linking mitochondrial metabolism and thermogenic gene expression, supporting its potential as a therapeutic target for enhancing energy expenditure in metabolic disease.

Iron deficiency (ID) impairs adrenocortical function, yet its underlying mechanism remains unclear. Here, we demonstrate that ID suppresses steroidogenic acute regulatory protein (StAR)-mediated adrenocortical steroidogenesis. In dietary ID mice, deferoxamine-treated mice and H295R cells, mineralocorticoid and glucocorticoid hormone production was significantly reduced. Transcriptomic analysis revealed that ID-induced suppression of steroidogenesis was primarily associated with StAR downregulation, which could be rescued by iron supplementation. Mechanistically, ID activated the ERK signaling pathway, leading to reduced StAR expression. Pharmacological inhibition of ERK restored both StAR protein levels and steroidogenic output. Collectively, our findings suggest that the ERK-StAR axis represents a potential regulatory pathway associated with ID-induced adrenocortical hypofunction.

The translocator protein (TSPO) is a mitochondrial outer membrane protein enriched in lipid-metabolic tissues, including white adipose tissue (WAT), but its physiological role in adipocytes remains poorly defined. Building on prior work that demonstrated a role for TSPO in mitochondrial fatty acid oxidation, we investigated whether TSPO contributes to adipocyte lipid homeostasis under metabolic stress. We employed a combination of in vivo and in vitro approaches using global Tspo knockout (Tspo-/-) mice, primary adipocyte cultures, and pharmacological TSPO-binding drugs to examine TSPO function. Our findings show that Tspo-/- mice exhibited increased gonadal and inguinal WAT mass and adipocyte hypertrophy following high-fat diet feeding in both sexes, with a modest late body weight increase in females, but no differences in feed intake. These changes were accompanied by suppression of key lipolytic genes, reduced circulating NEFA and glycerol levels, and altered expression of fatty acid oxidation genes. Lipidomic profiling showed no genotype-dependent changes, indicating impaired mobilization rather than altered lipid composition. In vitro, primary adipocytes derived from inguinal WAT of Tspo-/- mice exhibited enhanced lipid accumulation during differentiation and reduced expression of lipolytic genes. TSPO-binding drugs phenocopied this response in TSPO-expressing cells. Mechanistically, we identify protoporphyrin IX (PPIX), an endogenous TSPO ligand, as a suppressor of adipogenic and lipolytic programs. PPIX levels increase during adipogenesis, and its accrual inhibits both lipid accumulation and lipolytic programs. Our findings identify TSPO as a regulator of adipocyte lipid metabolism through a previously unrecognized TSPO-PPIX axis that influences lipid mobilization. This mechanism provides new insight into TSPO's role in adipose metabolic adaptation.

The estrogen receptor α (ERα) is a central regulator of 17β-estradiol (E2)-dependent physiological processes in reproductive and non-reproductive tissues. Deregulation of ERα signaling underlies distinct human pathologies, including breast cancer (BC) and the rare genetic disorder called estrogen insensitivity syndrome (EIS). In BC, somatic mutations of ESR1, the gene encoding ERα, emerge under endocrine therapy (ET) pressure and promote ligand-independent receptor activation, driving endocrine resistance and disease progression. In contrast, germline ESR1 mutations cause EIS by impairing ERα function and rendering peripheral tissues insensitive to circulating E2. Here, we review the structural and functional consequences of germline ERα point mutations identified in EIS and compare them with somatic ERα mutations described in BC. Despite their opposite effects on receptor activation, both classes of mutations disrupt distinct layers of ERα signaling, including ligand binding, DNA interaction, coactivator recruitment, nuclear trafficking, transcriptional regulation, and potentially extranuclear signaling. This comparative analysis reveals that perturbation of different mechanistic nodes within the ERα signaling network can converge on a shared phenotype of resistance. The results reviewed here underscore the modular nature of ERα signaling and highlight how structurally and mechanistically diverse mutations can produce convergent pathological phenotypes, providing insights into the generation of resistant ERα across distinct disease contexts.

Time-restricted feeding combats obesity by restoring the insulin/growth hormone ratio. Growth hormone and appetite are stimulated by ghrelin but inhibited by Leap2. Whether time-restricted feeding reduces weight gain through Leap2 inhibition is unknown. Ten-week-old male Leap2+/+ and Leap2-/- mice were randomly divided into four groups: Leap2+/+ normal diet (n = 6), Leap2+/+ high-fat diet (n = 6), Leap2-/- normal diet (n = 8), and Leap2-/- high-fat diet (n = 8). Body weight was measured weekly. In further experiments, the Leap2-/- high-fat diet mice were randomly assigned to time-restricted feeding or control for 10 weeks. Metabolic parameters were monitored; growth hormone profiles over 6 h were obtained at week 5, and insulin and glucose tolerance tests were performed at week 8 or 9. Expression of metabolism-related genes was assessed in the liver, white adipose tissue, and brown adipose tissue after 10 weeks. Body weight was significantly increased in Leap2-/- mice fed a normal diet and was further increased in both Leap2-/- and wild-type mice by the high-fat diet, with greater weight gain in Leap2-/- mice. Time-restricted feeding decreased body weight, fat weight, and liver weight; improved growth hormone pulsatility, insulin sensitivity, and glucose tolerance; and enhanced lipid metabolism, oxygen consumption, and physical activity during the dark phase, while altering the expression of genes related to glucose and lipid utilization. It decreased adipocyte size and prevented liver fat accumulation. Although Leap2-/- mice gained more weight during high-fat diet feeding, time-restricted feeding improved growth hormone, insulin, glucose, and lipid metabolism without changing total caloric intake over the 10-week protocol, similar to that observed in wild-type mice.

The NR4A nuclear receptor family (NR4A1, NR4A2, and NR4A3) comprises stimulus-responsive orphan nuclear receptors expressed in endocrine tissues, including the anterior pituitary gland. However, their functional roles in lactotrophs remain poorly understood. Because prolactin (PRL) secretion varies markedly across reproductive states, it provides a useful physiological model for investigating gene expression changes associated with distinct secretory conditions. In this study, we examined the expression patterns of the three Nr4a genes in the rat pituitary under physiological and pharmacological conditions associated with altered PRL secretion and evaluated the contribution of each NR4A family member to PRL secretion. Pituitary Nr4a gene expression increased in parallel with elevated PRL secretion during pregnancy and lactation. In contrast, Nr4a expression declined after weaning as PRL secretion decreased, and the nocturnal increase in Nr4a expression observed during early pseudopregnancy was absent after mid-pregnancy. Pseudopregnancy was also associated with an overnight increase in PRL secretion accompanied by increased pituitary Nr4a expression. These coordinated changes in PRL secretion and Nr4a expression were suppressed by dopaminergic inhibition in vivo and in primary pituitary cultures, whereas oxytocin transiently enhanced PRL secretion and Nr4a expression. Importantly, knockdown of Nr4a2, but not Nr4a1 or Nr4a3, significantly reduced PRL secretion without affecting Prl mRNA expression. These findings demonstrate that NR4A family members are associated with physiological PRL secretory states and identify NR4A2 as a selective regulator of PRL secretion at the level of hormone release rather than transcription.

Vitamin D deficiency is highly prevalent in alcohol-associated liver disease and may contribute to metabolic and inflammatory dysregulation in alcoholic steatohepatitis (ASH). To examine the hepato-metabolic actions of vitamin D receptor (VDR) activation in ASH, we evaluated calcipotriol, a VDR agonist, in male C57BL/6N mice fed a 5% ethanol-containing Lieber-DeCarli diet. Calcipotriol (20 μg/kg) reduced intrahepatic triglyceride accumulation and serum alanine aminotransferase activity, indicating attenuation of alcohol-induced liver injury. Integrated transcriptomic, metabolomic and biochemical analyses showed that VDR agonism suppressed hepatic lipogenic programmes, including de novo lipogenesis, and improved alcohol-induced metabolic derangements. Calcipotriol also reduced oxidative injury and endoplasmic reticulum stress, as evidenced by lower hepatic protein carbonyl content and reduced p-eIF2α, XBP1s, CHOP, ATF4 and BiP expression, together with diminished inflammasome-associated inflammatory signalling. Metabolomic profiling further showed partial restoration of hepatic metabolic homeostasis by calcipotriol, as evidenced by increased choline, uridine monophosphate and taurine levels. These findings identify calcipotriol as an endocrine-metabolic modulator of ASH and support VDR activation as a mechanistically relevant therapeutic strategy for alcohol-induced liver injury.

Diabetic nephropathy (DN) is a leading cause of chronic kidney failure. We hypothesized that mitochondrial Akt1 dysfunction in renal proximal tubules plays a pathogenic role in DN development and that its activation may reverse DN progression. To study this signaling pathway, we generated a transgenic mouse model harboring a renal tubule-specific, tamoxifen-inducible, mitochondria-targeted constitutively active Akt1 (KMCAKT). Type 2 diabetes was induced by a high-fat, high-fructose diet (HFFD) for 40 weeks. Renal histology and function were evaluated, and glucose metabolism was assessed using dynamic glucose testing. We found that HFFD feeding resulted in the development of DN in control non-induced KMCAKT mice, whereas KMCAKT mice with constitutively active mitochondrial Akt1, induced by tamoxifen injection (TAM), exhibited a significant improvement in kidney dysfunction and histology. Urinary albumin, fasting plasma BUN levels, fibrosis, and Jablonski scores were all markedly improved in HFFD-TAM-KMCAKT mice compared with controls, while levels of α-smooth muscle actin (αSMA) and transforming growth factor-β1 (TGFβ1) were significantly reduced. HFFD-TAM-KMCAKT mice exhibited lower fasting blood glucose and improved oral glucose tolerance, while basal and stimulated insulin levels were higher, along with increased beta cell mass and insulin secretion (HOMA-β) compared with controls. Hyperglycemic clamp studies confirmed increased insulin secretion in HFFD-TAM-KMCAKT mice. We conclude that tubular mitochondrial Akt1 plays a key role in DN progression. Restoring tubular mitochondrial Akt1 signaling may represent a novel approach to reverse the development of chronic kidney disease. We also identified previously unrecognized metabolic cross talk between renal tubular mitochondrial Akt1 and pancreatic insulin secretion that may modulate systemic glucose homeostasis.