Timo Dirk Müller

Glucagon-like peptide-1 (GLP-1)-based therapies marked a major breakthrough in obesity pharmacotherapy, while subsequent advancements targeting multiple entero-pancreatic hormones now deliver weight loss previously achievable only with bariatric surgery, alongside improvements in obesity-related complications. Despite this progress, significant challenges persist, including reduced efficacy in diabetic populations, gastrointestinal adverse effects, and high costs that drive a real-world adherence gap. Consequently, next-generation therapies, including receptor polyagonists, oral formulations, and small-molecule incretin mimetics with optimized pharmacokinetic profiles, are being developed to enhance efficacy, tolerability, and accessibility while maintaining safety. However, weight regain after treatment cessation remains a critical hurdle. Growing evidence underscores the importance of sustained lifestyle interventions and muscle mass preservation to facilitate weight stabilization. Concurrently, research is heavily focused on identifying the biological drivers of weight regain, such as altered neuroregulation, metabolic adaptation, and adipose tissue remodeling. This review examines the current landscape, limitations, and emerging strategies of obesity pharmacotherapy.

Obesity is a chronic, relapsing disease driven by complex interactions between genetic, environmental, neuroendocrine and behavioural factors. The advent of incretin-based therapies and the expansion to multi-receptor agonist peptides targeting glucagon-like peptide 1 (GLP1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin receptors has transformed obesity treatment, demonstrating average weight loss of more than 20% in humans and improvements in a broad range of obesity-related comorbidities. In this Review, we trace the recent evolution of obesity pharmacotherapy from GLP1 receptor agonists to next-generation multi-receptor agonists, alongside strategies that incorporate oral formulations, weight-loss quality approaches and tissue-specific drug targeting. We outline major translational and biological challenges, identify key gaps for future research and discuss emerging approaches aimed at achieving durable and scalable obesity treatment.

There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R–GIPR co-agonism is effective in the management of obesity and type 2 diabetes ^1,2 , and lanifibranor—a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ—is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis ³ . Here, seeking to further improve the metabolic efficacy of GLP-1R–GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R–GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1–GIP–lanifibranor is indistinguishable from GLP-1–GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1–GIP–lanifibranor outperforms GLP-1R–GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1–GIP–lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1–GIP–lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.

Binge-eating disorder (BED) is the most common eating disorder worldwide and carries life-altering comorbidities. While genetic and environmental risk factors have been identified, the mechanisms that determine inter-individual susceptibility to BED remain largely unknown. Here, we demonstrate that developmental dosage of the DNA hydroxymethylase Tet1 defines stable inter-individual differences in binge-eating susceptibility. In mice, midbrain dopaminergic neurons of the ventral tegmental area (VTA ^DA ) are essential for the induction of addictive binge-eating behavior, express high levels of Tet1 , and undergo rapid and widespread DNA hydroxymethylation remodeling upon experimental binge eating. Strikingly, Tet1 haploinsufficiency creates pronounced inter-individual variation in binge-eating susceptibility even among genetically identical mice, which we trace to reduced connectivity between the prelimbic medial prefrontal cortex (mPFC ^PL ) and the VTA. Chemogenetic inhibition of mPFC ^PL →VTA projections reduces binge-eating susceptibility, whereas EGR1-guided re-activation of TET1 in VTA dopaminergic neurons restores susceptibility, supporting a causal role for this axis. Importantly, TET1 promoter methylation in patients associates with binge-eating behavior and reward-circuit function, suggesting conservation of this regulatory network in humans. Collectively, these findings identify Tet1 dosage as a novel regulator of binge-eating susceptibility and provide a mechanistic basis for how inter-individual differences in behavior are established.

Background: The Allan-Herndon-Dudley syndrome (AHDS) is a rare, X-linked human genetic disorder caused by mutations in the monocarboxylate transporter 8 (MCT8), essential for thyroid hormone (TH) transport across the blood-brain-barrier. The resulting central TH deprivation disrupts brain maturation and function, leading to intellectual disability and movement disorders. Cortical development, highly dependent on TH, is particularly affected and contributes significantly to AHDS pathologies. Methods: To elucidate disrupted cortical processes, we conducted single nucleus RNA sequencing in a mouse model engineered to mimic the central TH deficiency characteristic of human AHDS. This murine AHDS model features the concomitant deletion of both MCT8 and OATP1C1, a T4 transporter largely absent in human brain capillaries that in mice plays a role in TH transport. The phenotype of dKO mice bears striking resemblance to the pathologies observed in human AHDS patients. Results: Single nuclei were isolated from the cortex and attached striatum of 21-day old WT and MCT8/OATP1C1 dKO mice and sequenced using the 10x Genomics workflow. Cell proportion analyses on the resulting 48 clusters suggested elevated numbers of GABAergic striatal D1 and D2 neurons in the dKO mice. Diminished levels of mature oligodendrocytes coincided with a bifurcation within the oligodendrocyte lineage trajectory, leading to distinct subpopulations of WT and dKO oligodendrocytes. Differentially expressed gene (DEG) patterns align poorly with Slc16a2 and Slco1c1 mRNA levels in the respective clusters, but closely with prior published cortical bulk RNAseq data of mice with systemic hypothyroidism or MCT8/OATP1C1 deficiency. These parallels confirm the reliability of our data and provide new insights by pinpointing TH-responsive DEGs to specific cellular clusters. Moreover, inferred cell-cell communication using NeuronChat suggested a disbalance in GABAergic versus glutamatergic signaling. We further uncovered perturbed primary cilia formation in several GABAergic and glutamatergic clusters of the dKO cortex. Discussion: Molecular signatures and perturbations uncovered by our snRNAseq study reveal new molecular characteristics of the AHDS. The imbalance in GABAergic versus glutamatergic cell-cell-communication, perturbed primary cilia formation, and bifurcation of the oligodendrocyte lineage align with pathologies observed in AHDS patients and highlight the role of TH signaling in maintaining neuronal network homeostasis in the cortex.

Deficiency of the Monocarboxylate Transporter 8 (MCT8) severely impairs thyroid hormone (TH) transport into the brain, disrupting brain development as well as peripheral TH homeostasis. Studies assessing MCT8 expression patterns and tissue-specific pathologies induced by local TH-deficiency are often inconclusive due to unreliable antibody staining and the lack of functional tools to specifically target MCT8-expressing cells. For this purpose, we generated non-inducible Mct8-Cre and tamoxifen-inducible Mct8-CreERT2 mice. Mct8-Cre;Sun1-sfGFP mice demonstrated ubiquitous Sun1-sfGFP expression, due to early recombination driven by Mct8 gene expression at the stage of trophoblast implantation. Tamoxifen injection in 6-week-old Mct8-CreERT2 mice induced reporter expression specifically in Mct8-expressing cells in the brain and peripherally in liver, kidney, and thyroid, without leaky reporter expression in vehicle controls. Using vDISCO tissue clearing and 3D-imaging of GFP-nanobody-boosted mice, we further identified the sublingual salivary gland and the prostate as prominent Mct8-expressing organs. Nuclei from Mct8-expressing cells in the brain could selectively be enriched using fluorescence-activated nuclei sorting on Mct8-CreERT2;Sun1-sfGFP mice and characterized as choroid plexus cells and tanycytes. Our new inducible Mct8-CreERT2 line provides researchers with a tool to reliably mark, enrich, and characterize Mct8-expressing cells and to genetically modify genes specifically in these cells to study thyroid hormone transport and function.