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.

In eutherians, Insulin-like Growth Factor-I (IGF-I) and IGF-II exert insulin-like activity by interacting with type-I receptor. IGF bioavailability is finely regulated by six IGF-Binding Proteins (IGFBPs), IGFBP-1 to -6, which bind IGF-I and -II with high affinity but not insulin. Moreover, the Pregnancy-Asssociated Plasma Protein-A protease in able to specifically degrade IGFB-2, -4, -5. In the present work, we were interested in the evolution of this regulation of bioavailability in vertebrates, in particular in the question of the different nodes of appearance of IGFs, IGFBPs and PAPP-A in the tree of life. We confirmed that insulin-like/IGF peptides and their receptors appeared in non-vertebrate species, whereas IGFBPs first appeared in the vertebrate ancestor. More precisely, the first IGFBP that appeared was IGFBP-5 in amphioxus, whereas IGFBP-1, -2 and -3 apperaed in lamprey, IGFBP-4 in jawed fishes, and IGFBP-6 in teleost with a loss in birds. We also showed that the pregnancy-associated plasma protein A (PAPP-A) and PAPP-A2 metzincin proteases, which degrade several IGFBPs, might have appeared in non-vertebrates and that their two inhibitors, proMBP and STC, probably appeared before both proteases. Interestingly, the cleavage sites of IGFBP were restricted to some species : for IGFBP-2 and -5, it was present in mammals, birds and reptiles, but not in amphibians and fishes; for IGFBP-4 in Mammals only. Another important point is that another insulin-like peptide-binding protein found in the fruit fly, IMPL2, has probably disappeared in vertebrates.

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.

Excessive mineralocorticoid receptor (MR) activation in the heart and vasculature leads to pathological effects such as extracellular matrix accumulation, oxidative stress, and sustained inflammation. While MR's role in cardiovascular and renal systems is well understood, MR signaling has also been implicated as a key driver of homeostasis and pathological changes in several other body systems, including skeletal muscle and adipose tissue. The glucocorticoid receptor (GR) and MR are structurally and functionally linked, sharing 95% similarity in DNA-binding domains and recognizing many of the same hormone response elements (HREs) as transcriptional regulators of target genes. The role of GR in bone has been defined through several mechanistic studies, whereas the role of MR in bone is understudied. Because mineralocorticoid signaling regulates renal sodium and calcium handling, chronic hyperaldosteronism may indirectly disrupt skeletal homeostasis through urinary calcium wasting and secondary alterations in parathyroid hormone signaling. Furthermore, MR inhibition through MR antagonists (MRAs) has been associated with beneficial skeletal effects, particularly in settings of hyperaldosteronism and 11β-HSD2 deficiency. In this review, we present historical and current scientific findings on the role of genomic MR signaling in bone and extra-skeletal tissues that may be involved in crosstalk with the skeletal system. Furthermore, we also highlight the availability of tools to study MR signaling in the context of the musculoskeletal system.

Intestinal barrier dysfunction and gut microbiota dysbiosis contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). However, the effects of empagliflozin on the gut microbiota-intestinal barrier axis remain incompletely understood. This study investigated whether empagliflozin improves intestinal barrier integrity and gut microbiota profiles in a streptozotocin (STZ)-induced murine model of T2DM. Male C57BL/6 mice were fed a high-fat diet followed by STZ injection to induce T2DM and then treated with empagliflozin (10 mg/kg/day) for 8 weeks. Intestinal barrier-related proteins were assessed by immunofluorescence and western blotting. Gut microbial profiles were analyzed using 16S rRNA gene sequencing. Short-chain fatty acids (SCFAs), lipopolysaccharide (LPS), and inflammatory cytokines were quantified by GC-MS and ELISA. Empagliflozin treatment significantly reduced fasting blood glucose levels and attenuated weight gain in diabetic mice. Diabetic animals exhibited compromised intestinal barrier structure, accompanied by decreased tight junction protein expression (Claudin-1 and ZO-1) and enhanced TLR4/MyD88/NF-κB signaling, which were substantially alleviated following empagliflozin treatment. Concurrently, elevated inflammatory cytokines (IL-1β, IL-6, and TNF-α) and LPS levels were significantly reduced following empagliflozin treatment. Microbiome analyses revealed treatment-associated reorganization of gut microbial communities, including altered β-diversity patterns, shifts in diabetes-related taxa, and modified microbial interaction networks. In addition, empagliflozin increased fecal concentrations of key SCFAs, particularly butyrate and isohexanoate. Empagliflozin was associated with improved metabolic parameters, enhanced intestinal barrier integrity, reduced inflammation, and alterations in gut microbiota composition and predicted metabolic activity. Modulation of gut homeostasis may contribute to the therapeutic benefits of empagliflozin in T2DM.

The vitamin D receptor (VDR) is a ligand-activated nuclear receptor that mediates the biological actions of vitamin D and is a critical regulator of mineral homeostasis, cellular differentiation, immune function, and metabolism. VDR is a high-affinity intracellular binding protein for the most active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D). Early biochemical and molecular studies established VDR as a member of the nuclear receptor superfamily, functioning as a transcription factor that heterodimerizes with the retinoid X receptor and binds vitamin D response elements to regulate gene expression. Since the cloning of the VDR gene in the 1980s, characterization of its structural domains and identification of coregulators significantly advanced understanding of its genomic mechanisms of action. Over the past several decades, research has expanded the scope of VDR biology beyond classical calcium and phosphate metabolism. Genome-wide binding analyses and transcriptomic studies have revealed extensive VDR cistromes and context-dependent gene networks across diverse tissues. These advances have positioned VDR as a key factor linking vitamin D availability to tissue-specific outcomes. Despite substantial progress, fundamental questions remain, including mechanisms governing tissue-specific VDR actions, integration of genomic signaling pathways, and the role of VDR in complex diseases, such as cancer, autoimmune disorders, and aging. In addition, how VDR function is modulated by chromatin context, metabolic state, and the microbiome remains incompletely understood. Here, we summarize what is known about these actions of VDR and its history of discovery. Addressing these questions will be essential for translating mechanistic insights into improved therapeutic strategies targeting the vitamin D axis.

Obesity is characterized by chronic inflammation and impaired glucose homeostasis. Regulatory T cells (Tregs) preserve immunometabolic balance, and their reduction contributes to metabolic disturbances. Although IL-2/anti-IL-2 complex (IL-2C) and hyperbaric oxygen (HBO) therapy expand Tregs, their combined effects on obesity remain unclear. Male C57BL/6 mice were fed a low-fat diet (LFD) or a high-fat diet (HFD) for 16 weeks and treated with IL-2C and/or HBO. Both interventions significantly reduced HFD-induced body weight (9-22%, P < 0.05) independent of caloric intake, with no significant changes in LFD groups. Glucose tolerance and insulin sensitivity improved, showing significant reductions in IPGTT and IPITT area-under-the-curve values (20-25% and 30-35%, respectively; P < 0.05) compared with the HFD control. Combination therapy produced the most consistent metabolic improvements. Histological analysis demonstrated reduced adipocyte hypertrophy and crown-like structures in epididymal adipose tissue (P < 0.05). Treatments restored CD4+FoxP3+ Tregs, suppressed pro-inflammatory M1 macrophages, and decreased hypoxia-inducible factor-1α expression (P < 0.05). Consistent with these findings, histological examination revealed tissue-specific structural remodeling, characterized by restored multilocular adipocytes in iBAT and reduced adipocyte hypertrophy in iWAT under HFD conditions. These findings suggest that IL-2C and HBO improve immunometabolic dysfunction associated with obesity, in parallel with favorable adipose tissue remodeling and metabolic adaptation. Thus, IL-2C and HBO may represent complementary therapeutic strategies for enhancing metabolic health.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern worldwide. Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions. Notably, this phenotype was found exacerbated in mice with genetic or pharmacological inhibition of the master transcriptional regulator of energy metabolism, nuclear receptor ERRα. In this study, we show that combining antimalarial drug chloroquine with rapamycin attenuates the severity of hepatic lipid deposition observed with rapamycin monotherapy. Bulk mRNA-seq profiling showed that chloroquine co-injection reverses the upregulation of a large proportion of genes linked to lipid metabolism homeostasis found induced by rapamycin alone. Interrogation of these genes for direct transcriptional regulators identified ERRα among top candidates. Using a mouse model with genetic ERRα ablation, we demonstrate a crucial dependency on ERRα activity for the observed amelioration of rapamycin-induced hepatic steatosis by chloroquine addition. In ERRα-null liver, chloroquine failed to reverse and, in some instances, aggravated the upregulation of lipid metabolism genes by rapamycin, with evidence linking the impaired management of hepatic lipid overload to the underlying mitochondrial dysfunction. Together, these findings underscore a critical role of ERRα in reversing MASLD.

Polycystic ovary syndrome (PCOS), a common endocrine-metabolic disorder, lacks effective therapeutic options. Granulosa cell (GC) apoptosis and mitochondrial dysfunction are critical drivers of ovarian dysfunction in PCOS, yet targeted therapies are scarce. Scutellarin, a bioactive flavonoid, is a promising but unexplored candidate for treating PCOS. We investigated scutellarin's effects in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model and in DHEA-treated human granulosa-like KGN cells. We assessed metabolic and reproductive parameters, ovarian histology, and fertility and examined molecular mechanisms using transcriptomics, qRT-PCR, and western blotting. Apoptosis and mitochondrial function were evaluated via TUNEL staining, flow cytometry, and real-time mitochondrial assays. We found that scutellarin treatment was associated with improved metabolic phenotypes in PCOS mice, including glucose intolerance and insulin resistance, a normalized estrous cycle, lower serum testosterone and luteinizing hormone levels, better ovarian morphology, and enhanced fertility. Mechanistically, scutellarin correlated with reduced ovarian GC apoptosis and modulation of BCL2, BAX, and cleaved caspase-3. Transcriptomic analysis identified the PI3K/Akt signaling pathway as a key mediator, and scutellarin dampened its abnormal activation in DHEA-induced PCOS in vivo and in vitro. Furthermore, scutellarin was associated with improved mitochondrial function in DHEA-treated KGN cells, evidenced by reduced ROS production and restored membrane potential. We conclude that scutellarin is associated with the amelioration of metabolic and reproductive abnormalities in a PCOS mouse model, correlating with reduced GC apoptosis and improved mitochondrial function. By modulating these cellular defects, scutellarin offers potential dual benefits on ovarian and systemic dysfunctions, highlighting its value for clinical investigation and providing novel mechanistic insights.