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.

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.

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.