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 diabetes1,2, 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 steatohepatitis3. 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.

Mitochondrial uncoupling proteins (UCPs) play central roles in vertebrate energy metabolism, with UCP1 specializing as a thermogenic effector in placental mammals. Comparative genomics demonstrated that UCP1, UCP2, and UCP3 originated prior to the emergence of endothermy, suggesting that their ancestral functions evolved in ectothermic vertebrates. Here, we investigated the genomic organization, conserved synteny, and mRNA expression of all three UCP paralogs and homoeologs in the allotetraploid amphibian Xenopus laevis. Comparative genome analyses revealed that all three UCP paralogs and their long (L) and short (S) homoeologs were retained following polyploidization, although local rearrangements were evident for neighboring genes at the UCP2/UCP3 locus. Quantitative expression analyses across adult frog tissues revealed pronounced tissue specificity, with predominant expression of UCP1 and UCP2 in kidney, UCP3 in muscle, and differences in UCP2 homoeolog expression levels. Together, these findings establish a framework for UCPs in an amphibian model organism, primarily linking them to energetically demanding tissues.

Scientific progress across biological disciplines has been driven largely by advances in experimental resolution. In particular, physiological research has evolved from classical measurements at the level of whole organisms and organs to molecular analyses in single cells and organelles, where the regulation of gene expression and protein activity is interrogated to elucidate mechanisms underlying homeostasis. Modern physiology has successfully integrated biomechanics, electrophysiology, and biochemistry to resolve processes at subcellular scales. The next frontier lies in the integration of molecular mechanisms at the level of individual proteins, which directly couple regulatory signals to molecular function, for example, by mediating the transport of ions across biological membranes. From a translational perspective, intelligent drug design ultimately depends on precise knowledge of structure–function relationships in the target protein. Any comprehensive understanding of physiological processes, “the full picture,” remains incomplete if these molecular “pixels,” which form the fundamental basis of physiological function, are overlooked.

Uncoupling Protein 1 (UCP1) is a mitochondrial protein which drives thermogenesis in brown adipose tissue. UCP1 facilitates the dissipation of the proton gradient as heat and plays a critical role in energy expenditure and metabolic regulation. We employ advanced molecular simulations and mutagenesis to reveal the mechanism of UCP1-mediated proton and fatty acid (FA) transport. We demonstrate that FAs bind spontaneously to UCP1's central substrate-binding site. In the binding site, a proton transfer to the FA is facilitated by a key aspartate residue (D28) and a coordinating water molecule. The protonated FA exits UCP1 through a well-defined pathway, and releases its proton into the mitochondrial matrix. UCP1 then facilitates the return of deprotonated FAs to the intermembrane space. Nucleotide binding disrupts this mechanism by inducing conformational changes in the transmembrane helices and obstructing the FA return pathway. Our mechanism explains every step of the transport cycle, is supported by simulation and biochemical data, and explains a diverse set of biochemical data about the transport mechanisms in UCP1 and its analogues: ANT, UCP2, and UCP3.

Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJKO mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2 alpha mediated stress response. The pivotal role of eIF2 alpha is scrutinized by in vivo CRISPR deletion of eIF2 alpha in MCJKO mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.

The ability to enhance heat production in response to prolonged cold exposure (cold acclimation capacity) is a key physiological adaptation in some endotherms, such as eutherian mammals, owing to a specialized mechanism of adaptive non-shivering thermogenesis in brown adipose tissue, mediated by uncoupling protein 1, which seems to be absent in marsupials and birds. Phenotypically, it is unclear whether these endotherms lack cold acclimation capacity or whether they have other facultative heat production mechanisms. To test for differences in thermal acclimation capacity, we analyzed published studies measuring maximum metabolic rates following cold acclimation. Using generalized linear models, phylogenetic generalized least squares and meta-analyses, we compared placentals, marsupials and birds. The results consistently indicated that placental mammals exhibit significantly greater cold acclimation capacity than marsupials and birds. Meta-analysis revealed maximum rate of oxygen consumption responses as being 101.8% higher in placentals than those in birds and 301.2% higher than those in marsupials. Our findings suggesting superior thermogenic plasticity in placental mammals reflect unique evolutionary adaptations, permitting these animals to thrive in seasonally cold environments, which is especially important when migration capacity is limited. Birds, however, with lesser migratory restrictions, would have prioritized the insulating capacity of feathers as an evolutionary solution to the cold. Marsupials, without the innovation of adaptive thermogenesis, would have a geographical distribution restricted to non-extreme areas.

Background: Type 2 diabetes (T2D) represents a growing global health challenge, with its prevalence and associated metabolic complications rising sharply over the past two decades. Although the pathogenesis of T2D is complex and influenced by lifestyle and (micro)environmental factors, genetic constituents have been considered major predisposing factors. Recent literature shows significant individual variations in both the progression of T2D and the efficacy of antidiabetic drugs. These individual variations are expected to emanate from the inherent genetic make-up and potential epigenetic modifications by environmental factors.

Hypothesis: It has been proposed that altered metabolism (including cellular bioenergetic mechanisms) provides protection from T2D. Moreover, several researchers have proposed that proteins regulating cellular bioenergetics, for example, involved in adaptive thermogenesis, represent good targets to counter T2D. Therefore, we thoroughly searched the literature on genetic variability associated with T2D in this review.

Results: We could only find genes involved in (1) insulin secretion (INS, PDX1, ABCC8, KCNJ11, KCNQ1, CDKAL1, IGFBP2) and (2) cellular bioenergetics in insulin-responsive tissues (INSR, IRS, AKT, SLC2A4, TBC1D4, PPP1R3A, LEP, LEPR, ADIPOQ, TCF7L2, PPAR-γ, SLC30A8). Specific attention is given to diverse ethnic populations, in particular Indian subgroups where these genetic factors may display clearer association to T2D.

Conclusion: By emphasizing genetic predispositions, this review highlights the lack of studies on the genetic association of cellular bioenergetics proteins in T2D pathogenesis. It also underscores the potential for early detection, personalized management, and the development of targeted therapies for individuals with T2D across different genetic profiles.

Aim: Uncoupling protein 1 (UCP1) is the crucial protein for non-shivering thermogenesis in placental mammals, but the molecular mechanism of thermogenic proton transport is still unknown. Its histidine pair motif (H145 and H147) has been claimed as a critical element for proton translocation, leading to the paradigmatic “cofactor model” of the UCP1 thermogenic mechanism. The histidine pair motif is mutated (H145Q) in the naked mole-rat (NMR, Heterocephalus glaber) UCP1, suggesting disrupted thermogenic function in line with NMR's poor thermoregulatory abilities. Here, we investigated the functionality NMR versus mouse UCP1 to scrutinized the importance of the histidine pair motif. Methods: Respiratory analyses for UCP1 function were performed in isolated brown adipose tissue mitochondria from NMR and mouse. The histidine pair motif of NMR UCP1 was manipulated through mutations, ectopically overexpressed in HEK293 cells and subjected to plate-based respirometry for functional comparison. Results: Isolated BAT mitochondria of NMRs display guanosine diphosphate-sensitive respiration, indicative of thermogenically competent UCP1. Overexpressed wildtype NMR UCP1 demonstrates proton leak activity comparable to mouse UCP1. Neither restoration of the histidine pair motif nor full ablation of the motif through a double mutation affects UCP1-dependent respiration. Conclusions: The UCP1 variant of the NMR, a warm-adapted fossorial species, excludes the histidine pair motif as crucial for UCP1 thermogenic function. Collectively, we show that functional investigation into natural sequence variation of UCP1 not only casts new light on the thermophysiology of NMRs but also represents a powerful tool to delineate structure-function relationships underlying the enigmatic thermogenic proton transport of UCP1.