Obesity is a multifactorial disease characterized by an excessive and abnormal accumulation of body fat that results from both genetic and environmental factors. In this review, we revisited the literature on the variability of obesity-associated genes and their impact on the effectiveness of obesity treatment interventions. Individuals harboring variants of these genes were found to have either better or worse outcomes after weight loss therapies. The majority of the genetic variants were identified in genes that play a role in the leptin-melanocortin pathway (LEPR, NPY, POMC, MC4R, GHRL, GHSR, GLP-1R, BDNF), which regulates food intake and energy expenditure. Both these processes are key elements for energy homeostasis, therefore relevant for the success/failure of weight loss strategies. Some genetic alterations were found to modulate the outcomes of different weight loss interventions, while others were only linked to the effectiveness of bariatric surgery, according to the studies here included and available. Herein, we revisited the most relevant molecular data, with a primarily focus on human studies, concerning how the genetic background influences the outcomes of weight loss interventions. Our aim is to gather relevant information on the genetic data related to weight loss strategies that can be compelling to guide clinical decisions, setting realistic expectations, and ultimately improving the long-term health conditions of individuals with obesity.

Obesity is a global health crisis. Currently available treatments, while effective, show several undesirable side effects that hinder their long-term use. Herein, we investigated the anti-obesity potential of 6-benzylaminopurine (BAP), a plant hormone commonly used in agricultural settings to enhance plant development, in obese mice and mammalian cell models. Orally administered BAP induced significant weight loss in diet induced obese male and female CD-1 mice through sex-specific mechanisms involving appetite suppression, adipose tissue remodeling, and enhanced lipid utilization. Concurrently, BAP improves several metabolic parameters associated with obesity, including glucose tolerance, fasting blood glucose, hyperleptinemia, hyperinsulinemia, white adipose tissue browning, and liver health. In murine- and human-hypothalamic neuronal models, BAP suppresses the expression of feeding stimulating neuropeptide Y (Npy) and increases the anorexigenic pro-opiomelanecortin (Pomc). Using RNA-sequencing, we identified that BAP inhibits EGFR/ErbB2 and MEK/ERK/EGR1 signaling, whereas MEK/ERK inhibition is partially responsible for the in vitro effects of BAP, including Npy downregulation. Moreover, similar MEK/ERK inhibition was also shown to be involved in the induction of thermogenic markers, including uncoupling protein 1 (Ucp1), in 3T3-L1 derived adipocyte, indicating a consistent molecular mechanism of BAP across different cell types. Overall, our data showed that BAP could serve as an efficacious and alternative treatment avenue for obesity with a unique mechanism of action compared to currently available options.

The transcriptional repressor B cell lymphoma 6 (BCL6) is highly expressed in skeletal muscle. Although transcriptome-wide studies have shown BCL6 dysregulation in muscular dystrophies, investigations into its endogenous roles in muscle biology remain scarce. We therefore generated skeletal muscle-specific Bcl6 knockout (M-Bcl6 KO) mice and used adeno-associated virus to knockdown (KD) Bcl6 selectively in limb muscles of mice. In both models, Bcl6 deficiency led to reduced muscle mass and contractility. Single-nucleus RNA sequencing and biochemical analyses revealed upregulation of Socs2, and inhibition of the IGF1/AKT pathway. Mitochondrial respiration was significantly reduced in permeabilized myofibers upon Bcl6 KO and KD, and electron microscopy showed decreased mitochondrial density and altered morphology. Pathways regulating mitochondrial quality control were also downregulated. While Bcl6 KO did not significantly impair baseline treadmill running capacity, it blunted the adaptive response to endurance training. These findings demonstrate that Bcl6 is a critical regulator of skeletal muscle mass and mitochondrial bioenergetics, acting through transcriptional control of signaling and metabolic pathways essential for the maintenance of muscle mass and function.

Background and hypothesis

Lysosomal acid lipase (LAL) is so far the only known intracellular enzyme that is capable of hydrolyzing triglycerides and cholesteryl esters at an acidic pH inside the lysosome. Mutations in the LAL-encoding Lipa gene cause a rare autosomal recessive lysosomal storage disorder in humans with massive lipid accumulation. In mice, the loss of systemic LAL is associated with severe lipid accumulation, particularly in the liver and small intestine, accompanied by infiltration of lipid-filled CD68+-TREM2+ macrophages. We hypothesize that macrophages are among the key players in LAL deficiency and are responsible for lipid accumulation in the affected tissues.

Methods

We generated macrophage (mac)- and macrophage/enterocyte-specific (mac/int-) LAL KO mice and performed morphological, histopathological, and functional analyses under chow- and high-fat/high-cholesterol diet-fed conditions.

Results

We observed that neither macLAL-KO nor mac/int-LAL KO mice replicated the phenotype of whole-body LAL KO mice, as lipoprotein secretion, lipid absorption, and lipid accumulation remained unaffected. However, the absence of macrophage LAL ameliorated diet-induced obesity in both mouse lines. Notably, the lipid accumulation observed in the lysosomes of macrophages from whole-body LAL KO mice was absent in macrophages from macLAL-KO mice, attributable to residual LAL enzyme activity despite genetic ablation. Treatment of macrophages from whole-body LAL KO mice with conditioned medium of hepatocytes from macLAL-KO mice effectively prevented lipid accumulation.

Conclusion

These findings suggest that LAL secreted from hepatocytes, macrophages, and possibly other cell types in vivo corrects the phenotype of cell type-specific LAL deficiency, a key insight for guiding future gene therapy strategies.

Hypothalamic AgRP neurons are uniquely responsive to nutritional cues and play an important role in fuel homeostasis. To investigate the temporal relationship between the activity of these neurons and the glycemic response to an oral glucose load, we simultaneously monitored AgRP neuron activity (by fiber photometry in AgRP-IRES-cre mice) and the arterial glucose level, both before and after oral gavage (OG) of either water or glucose (0.5–2.5 g/kg). We report that the AgRP neuron response to an OG glucose load can be subdivided into two functionally distinct phases – one that begins prior to glucose delivery and a second that extends from peak inhibition through the return towards baseline. The ‘first phase’ appears to be anticipatory in nature and is also predictive of subsequent changes in glycemia, suggesting a role in the handling of an oral glucose load. To analyze the relationship between the second phase response and changes of glycemia, we employed a model that allows residual activity to be removed subsequent to the ‘first phase’ component. This analysis reveals that unlike the first phase, the degree of residual inhibition – the second phase – tracks the glycemic response. Moreover, this response is temporally aligned with the blood glucose (BG) rate of change (which is predictive of future BG levels), with AgRP neurons lagging BG rate of change by ∼5 min. We conclude that the AgRP neuron response to an oral glucose challenge consists of two distinct phases, each with its own determinants and metabolic implications: an initial anticipatory component that is predictive of the subsequent glycemic response, and a second phase that tracks the rate of BG change.

Objectives

Functional co- and tri-agonists at the receptors for GLP-1, GIP and glucagon effectively decrease body weight and hyperglycemia but are associated with adverse gastrointestinal effects related to GLP-1R agonism. Here we report the discovery that obesity can be reversed in the absence of a functional GLP-1R. It propelled the identification of a unimolecular GIPR:GCGR co-agonist lacking GLP-1 activity that corrects obesity in obese mice and rats.

Methods

Selective, dual, and triple sustained-action agonists at GIPR, GCGR and GLP-1R were used to assess body weight and glucose management in diet-induced obese (DIO) wildtype (WT) and GLP-1R knock-out (KO) mice. Indirect calorimetry and pair-feeding studies were used to characterize the magnitude of weight lowering specifically to suppression of food intake relative to energy expenditure.

Results

When used in physical co-mixture, selective GIPR agonism interacts with selective GCGR agonism to correct obesity and enhance glycemia in DIO mice. Retatrutide a balanced GLP-1R:GIPR:GCGR triagonist normalized body weight in obese GLP-1R KO mice. BWB3054, a fatty acylated GIPR:GCGR co-agonist, was identified as comparably potent as retatrutide to induce cAMP production at the mGIPR, and 4-fold reduced at mGCGR, but notably more than 100-fold diminished at mGLP-1R. Despite minimal relative GLP-1R potency, BWB3054 reduces excess body weight in obese DIO-mice to a similar degree as that observed for retatrutide in obese GLP-1R KO mice.

Conclusions

Correction of obesity and glycemia in mice without employing GLP-1 agonism was demonstrated by three independent methods (GLP-1R KO with retatrutide, GIPR:GCGR physical co-agonism mixture, and GIPR:GCGR covalent co-agonist) which advocate for the prospect that the adverse GI effects commonly associated with its use might be avoided.

Physical inactivity is highly prevalent worldwide and affects not only individual health but also the health of future generations. However, the impact of physical activity limited to the pre-mating period on offspring body weight and composition remains poorly understood. Using a voluntary wheel running approach in mice, we uncovered that post-weaning offspring body weight and composition are modulated by the combined effects of parental pre-mating exercise and parental age. During the mid-stage of lactation, pre-mating exercise in young parents reduced offspring visceral and subcutaneous adiposity, shortened tibial length in female offspring, and influenced offspring transcriptomic profiles of the hypothalamus, the central regulator of energy balance. Pre-mating exercise also led to modest long-lasting changes in the expression of lactation-related genes in maternal subcutaneous fat, as well as breastmilk nutritional composition and miRNA content. Nevertheless, these subtle milk-derived miRNA changes may influence offspring hypothalamic regulatory networks, providing initial evidence of how pre-mating maternal exercise may affect offspring hypothalamic development during the mid-stage of lactation. Together, these data provide a comprehensive understanding of how parental age and pre-mating exercise interact to shape post-weaning offspring body weight and composition, and offer deeper insights into how regular parental pre-mating exercise may influence offspring physiology and neurodevelopmental adaptations during lactation.

Therapy resistance is the leading cause of cancer-related deaths. Polyploid cancer cells mediate resistance through adaptive cell states transitions that promote survival and tumor recurrence. Here, we investigate metabolic differences between cisplatin-surviving polyploid cells and parental cancer cells using integrated fluxomics. Transcriptomic and proteomic profiling and extracellular flux analyses revealed that surviving cells upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that surviving cells utilize glucose to fuel the pentose phosphate pathway (PPP) for NADPH generation and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that surviving cells sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. In addition, pathway-centric transcriptomic analysis revealed that high PPP and antioxidant gene expression correlated with poor survival outcomes in patients across multiple cancer types, demonstrating the clinical prognostic value of PPP and antioxidant metabolism. These findings reveal a systems-level shift in metabolism that maintains antioxidant activity for cell survival, highlighting potential targets and treatment paradigms to overcome therapy resistance.

Background

CKM syndrome involves obesity, type 2 diabetes (T2D), chronic kidney disease (CKD) and cardiovascular disease (CVD). However, most preclinical models fail to reproduce the progressive renal and cardiac dysfunction characteristic of advanced CKM syndrome, limiting their ability to accurately reflect human disease.

Methods

Male uninephrectomized (UNx) KK-Ay mice received a high-fat diet (HFD) with or without the vasoconstrictor L-NNA for 13–16 weeks.

Results

UNx + HFD + L-NNA resulted in obesity, hyperglycemia and progressive kidney failure, indicated by a rapid increase in albuminuria and transient hyperfiltration followed by progressive glomerular filtration rate (GFR) decline over three months. Histopathological analysis revealed severe glomerular damage, fibrosis, inflammation and basement membrane thickening, most pronounced in UNx + HFD + L-NNA mice. Renal transcriptomics analysis revealed robust activation of inflammatory and fibrotic pathways, again most pronounced in UNx + HFD + L-NNA mice.

In the heart, UNx + HFD + L-NNA resulted in increased ejection fraction and fractional shortening, reduced end-systolic volume and increased left ventricular posterior wall thickness. Alongside pronounced right ventricular fibrosis, this phenotype points toward a phenotype of heart failure with preserved ejection fraction (HFpEF).

Conclusions

The UNx + HFD + L-NNA KK-Ay model reproduces key metabolic, renal and cardiac components of CKM syndrome. While obesity and hyperglycemia contribute substantially to disease burden, L-NNA-induced hypertension further exacerbates both renal decline and cardiac remodeling. Therefore, this model enables mechanistic investigation and evaluation of therapeutic strategies for CKM syndrome.

Graphical abstract

A multifactorial mouse model of cardiovascular-kidney-metabolic (CKM) syndrome. The model combines the KK-Ay genotype with uninephrectomy (UNx), high fat diet (HFD) and vasoconstriction (by L-NNA) to induce integrated dysfunction across three organ systems. At the cardiovascular level, a phenotype resembling heart failure with preserved ejection fraction (HFpEF) is observed, characterized by maintained cardiac output, increased fractional shortening, elevated ejection fraction and cardiac fibrosis. At the kidney level, there is a progressive decline in glomerular filtration rate (GFR) accompanied by marked albuminuria, glomerular damage, inflammation and fibrosis. Metabolically, the model develops obesity, hyperglycemia and mild hyperlipidemia develop in this mouse model. This multifactorial approach enables mechanistic studies of diabetic kidney disease progression within the CKM syndrome context.

Background

Ovarian cancer (OC) depends on lipids as fuel for metastasis and growth. We previously showed that cisplatin resistant (Pt–R) OC cells uptake higher amounts of fatty acids (FAs) compared to sensitive (Pt–S) cells, a process which facilitates cancer cell survival under cisplatin-induced oxidative stress.

Methods

Isogenic pairs of Pt–S and Pt–R OC cell lines were cultured in low serum conditions supplemented with either 50 μM oleic acid (OA, unsaturated) or 50 μM palmitic acid (PA, saturated) and used for viability assays, RNA-Sequencing, and cell cycle analysis. The effects of an OA enriched diet were assessed in intraperitoneal ovarian xenografts. The FABP inhibitor BMS-309403 was used to block lipid import in vitro and in vivo.

Results

Pt–R cells were less viable than Pt–S cells under serum depletion and OA rescued starvation induced inhibition of cell proliferation, with more significant effects in Pt–R compared to Pt–S cells. RNA-sequencing showed that OA promoted upregulation of cell cycle-related pathways, including G2/M checkpoints, driven by the transcription factor E2F1. Supplementation with OA increased S- and G2/M phase cell populations in both Pt–S and Pt–R cells (p < 0.05) and E2F1 inhibition reduced OA-induced cell proliferation. An OA enriched diet promoted the growth and peritoneal dissemination of Pt–R ovarian xenografts. When co-cultured with adipocytes, Pt–R cells expressed higher levels of FA transporter proteins FABP4 and CD36 compared to sensitive cells and FABP4 expression was upregulated in paired metastatic and recurrent vs. primary human ovarian tumors (p < 0.05). An FABP inhibitor sensitized OC cells to cisplatin and suppressed the in vivo growth of Pt–R xenografts and patient derived xenografts.

Conclusions

Pt–R OC cells harbor heightened dependence on unsaturated FAs compared to Pt–S cells and upregulate key transporters to increase FAs uptake. OA supports the proliferation of Pt–R cells in vitro and in vivo and a combination of carboplatin and FABP4 inhibitor reduces OC growth in vivo. These findings suggest that lipid composition may influence therapeutic response and raise important considerations for dietary guidance in patients with cancer.

Objective

Vagal sensory neurons (VSN) convey peripheral glycemic information to the brain, yet the specific pathways that continuously sense glucose fluctuations and regulate hormone secretion and feeding remain poorly defined. Here, we examined the anatomical and functional aspects of an integrated circuit originating in pancreatic β-cells, projecting through the nodose ganglion, and engaging the dorsal vagal complex to relay feedback to β-cells.

Methods

We performed monosynaptic viral fluorescent tracing, RNA sequencing, RNAscope, chemogenetics, optogenetics, neuronal silencing, automated glucose telemetry, feeding assays, neural activity measurements, glucose sensing, and intracellular calcium measurements using 2-photon microscopy.

Results

The vagal transcriptome exhibited metabolic state- and diet-dependent regulation of pathways involved in glucose sensing, insulin secretion, and glucose homeostasis. Viral tracing identified abundant VSN innervating β-cells, including a subset expressing cocaine- and amphetamine-regulated transcript (VSN^CART), whose activity was modulated by metabolic state and altered brainstem neuronal activity. VSN^CART stimulation increased acetylcholine and C-peptide secretion and lowered blood glucose in a metabolic state-dependent manner, whereas silencing impaired glucose-stimulated insulin secretion and induced glucose intolerance. VSN^CART activation suppressed food intake, while inhibition increased feeding, also in a metabolic state-dependent manner. C-Fos labeling and two-photon Ca²⁺ imaging revealed that VSN^CART neurons exhibit dose-dependent excitatory responses to glucose.

Conclusions

We identified a vagal sensory neuron–β-cell circuit and showed that VSN^CART neurons sense glucose to regulate insulin secretion, feeding behavior, and glucose homeostasis.

Graphical abstract

How the brain detects glycemic fluctuations to integrate hormone secretion and feeding behavior is unclear. Kumar et al. describe a vagus-brain-β-cell circuit identifying the vagus as a glucose-sensing hub. They show that a population of glucose excitatory vagal sensory neurons communicate with β-cells and the brain to regulate insulin secretion, feeding behavior and glucose homeostasis.

Long non-coding RNAs (lncRNAs) regulate multiple cellular processes. However, knowledge of the responses and regulatory functions of lncRNAs in physical exercise and training remains limited. As part of the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we conducted a comprehensive analysis of lncRNA expression patterns in 18 tissues after an 8-week progressive endurance training program in rats. The lncRNA expression pattern was largely tissue-specific. In total, 759 unique lncRNAs were found to be differentially expressed across all tissues, generally displaying lower abundance, shorter transcript length, and reduced GC content compared with protein-coding genes. The most pronounced changes were observed in white and brown adipose tissues, the hypothalamus, and the adrenal gland. In the two skeletal muscle tissues investigated, only two lncRNAs were commonly differentially expressed. White and brown adipose tissues revealed a correlation between upregulated differentially expressed lncRNAs and coding genes associated with immune regulation. We identified substantial sex differences in the lncRNA regulatory landscape in response to exercise training. This comprehensive tissue-specific characterization of exercise-responsive lncRNAs opens new avenues for understanding exercise as molecular medicine and may inform the development of lncRNA-targeted therapeutics that harness the beneficial effects of exercise.

Proper adipose tissue homeostasis is essential for systemic metabolic health, and its disruption promotes insulin resistance, inflammation, and cardiometabolic risk. Using unbiased systems genetics analyses in mice and humans identified ITIH5 as a central regulator of adipose homeostasis and whole-body metabolism. Acute administration of recombinant ITIH5 with pan-organ sequencing revealed a local adipose function, suppressing recruitment of circulating immune cells. Consistently, ITIH5 treatment in human endothelial cells reduced leukocyte recruitment. We generated temporally controlled, adipocyte-specific ITIH5 overexpression models in mice, which improved adipose architecture, glucose metabolism under high-fat diet conditions, while consistently reducing left ventricular mass and cardiac output regardless of dietary group. Spatial transcriptomics of adipose tissue showed that elevated ITIH5 signaling to endothelia selectively impairs dendritic cell (DC) and B cell activation pathways. Collectively, these findings identify a mechanism whereby natural genetic variation in an adipocyte-secreted protein modulates endothelial–immune interactions in fat, influencing cardiometabolic homeostasis in a diet-dependent manner.

Background

Maternal obesity increases the risk of congenital anomalies and later-life metabolic disease in offspring. Still, underlying mechanisms remain unclear, particularly in extraembryonic lineages at the maternal–fetal interface, which remain poorly studied.

Methods

We jointly profiled gene expression and chromatin accessibility in single nuclei from mouse embryos and extraembryonic tissues in a diet-induced obesity model at embryonic day 8.5, when multiple organogenesis programs are underway.

Results

This analysis generated an atlas of 36 cell lineages, including derivatives of all three germ layers and trophoblast populations. Lineage allocation was preserved in embryos from obese dams. However, transcription was widely dysregulated. Oxidative phosphorylation genes were broadly suppressed, and genes involved in hypoxia, cytoskeleton remodeling, and cell migration were enriched among upregulated pathways. Chromatin accessibility changed in a few lineages, most notably in extraembryonic visceral endoderm and parietal trophoblast giant cells. Differently accessible chromatin was enriched in binding motifs for retinoic acid receptors. Indeed, genes involved in retinol and lipoprotein transport were suppressed, and RNA in situ hybridization confirmed reduced expression of retinol transporters Ttr, Rbp4, and Stra6, and lipoprotein transporter Apoa1 in visceral yolk sac.

Conclusion

Obesity during pregnancy causes early transcriptional dysregulation that impairs retinoic acid and lipoprotein transport at the maternal–fetal interface, suggesting a mechanism through which maternal obesity could influence long-term developmental outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, steatohepatitis (MASH), feature excessive hepatic fat accumulation, yet the relative contributions of dietary vs. endogenous fats and their interactions has remained enigmatic. Here, we identify the endoplasmic reticulum–associated E3 ubiquitin ligase MARCHF6 as a pivotal regulator of hepatic lipid metabolism. Global or hepatocyte-specific deletion of Marchf6 induced spontaneous accumulation of triglycerides and cholesteryl esters under chow-fed conditions, revealing a cell-autonomous hepatic defect independent of caloric excess. Loss of MARCHF6 stabilized its substrate squalene epoxidase (SQLE), enhancing sterol pathway flux while concomitantly activating the SREBP1-associated lipogenic transcriptional program and increasing lipoprotein clearance. Accordingly, lipidomic analyses demonstrated remodeling of the hepatic lipidome towards polyunsaturated, long-chain neutral lipids, consistent with increased lipogenesis-driven NADPH consumption. In line with this, pharmacological inhibition of the oxidative pentose phosphate pathway reduced lipid accumulation in MARCHF6-deficient human hepatocytes. Congruently, transcriptomic data from human MASLD/MASH patients revealed reduced hepatic MARCHF6 expression alongside an increase in that of the lipogenic genes SREBF1, FASN, and SCD1. Overall, these data establish MARCHF6 as a multifaceted gatekeeper that integrates sterol turnover, NADPH usage, and lipogenesis to maintain hepatic lipid homeostasis.

The failure of hyperleptinemia to decrease adiposity in common forms of obesity has led to the notion that impaired leptin receptor (LepRb) signaling (“leptin resistance”) might cause obesity. Because LepRb transcriptional signaling plays a central role in leptin action, we defined the control of gene expression in hypothalamic LepRb neurons in diet-induced obese (DIO) mice and in response to changes in circulating leptin. We found that LepRb neurons from DIO mice exhibited transcriptional changes similar to those induced by exogenous leptin. We also examined electrical activity in LepRb neurons from DIO mice, focusing on LepRb neurons in the ventromedial hypothalamic nucleus (VMN). This analysis revealed larger membrane depolarizations in response to current injection for VMN LepRb neurons from DIO mice. This effect was recapitulated by hyperleptinemia in vivo or exposure to elevated leptin ex vivo. Hence, hypothalamic LepRb neurons exhibit increased cellular leptin responses due to hyperleptinemia in DIO animals. These findings contradict the notion that impaired cellular leptin action underlies the development of DIO but rather suggest that increased leptin action drives DIO-associated changes in hypothalamic LepRb neuron function.

Objectives

Human genetic studies have identified GPR75 loss-of-function variants to be strongly protective against obesity, establishing GPR75 as a compelling therapeutic target. However, critical questions remain regarding the translational potential of GPR75 inhibition. These include whether adult-onset inhibition can reverse established obesity and which tissue compartments mediate weight loss. Here, we address these fundamental questions using novel genetic mouse models.

Methods

We generated whole-body inducible Gpr75 knockout mice to assess the effects of adult-onset Gpr75 deletion. Adult Gpr75flox/flox; R26-CreERT mice were treated with tamoxifen either pre-obesity and then challenged with high-fat diet (HFD) to evaluate protection from weight gain, or post-obesity establishment to evaluate weight loss. The role of brain Gpr75 was determined using neonatal intracerebroventricular injection of adeno-associated viruses carrying artificial microRNAs targeting Gpr75, and weight gain on HFD was evaluated. Both male and female mice were examined.

Results

Adult-onset Gpr75 knockout prevented diet-induced obesity when induced prior to HFD challenge, indicating the body weight phenotype is independent of developmental effects. Strikingly, Gpr75 deletion induced in obese mice produced robust weight loss, demonstrating the potential for therapeutic efficacy. Body composition analysis revealed specific fat mass reduction with complete lean mass preservation in Gpr75 inducible knockout mice. The body weight differences occurred with no change or only modest reductions in food intake. Postnatal brain-targeted Gpr75 knockdown was sufficient to confer significant protection from diet-induced obesity, with efficacy correlating to knockdown efficiency.

Conclusions

These data provide compelling genetic evidence that Gpr75 inhibition in adulthood can achieve substantial weight loss with selective fat mass reduction and lean mass preservation, operating through a mechanism that extends beyond appetite suppression alone. In addition, Gpr75 action in the postnatal brain plays a critical role in mediating these effects. Our findings de-risk a major translational concern, i.e., the developmental impacts of GPR75 on body weight regulation, and support the exploration of brain-penetrant GPR75 inhibitors as a novel obesity therapeutic strategy.