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In mice, a low-protein diet leads to a gut-microbiota-driven remodelling of adipose tissue towards brown fat, showing that gut microorganisms have a role in detecting and responding to a lack of protein.

The field of bioenergetics is rapidly expanding with new discoveries of mechanisms and potential therapeutic targets. The 2023 Keystone symposium on ‘Bioenergetics in Health and Disease’, which was jointly held with the symposium ‘Adipose Tissue: Energizing Good Fat’, consisted of a powerhouse line-up of researchers who shared their insights.

Granath-Panelo and Kajimura review emerging evidence of mitochondrial heterogeneity in different contexts and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

Adipose tissues have a central role in energy homeostasis, as they secrete adipokines and regulate energy storage and dissipation. Novel adipokines from white, brown and beige adipocytes have been identified in 2016. Identifying the specific receptors for each adipokine is pivotal for developing greater insights into the fat-derived signalling pathways that regulate energy homeostasis.

The mouse develops a developmentally and functionally distinct, non-canonical beige fat cell type as an adaptation to cold ambient temperature.

Breast cancer cells interact with neighbouring adipocytes, but the mechanisms are not fully understood. Here, the authors show that triple-negative breast cancer (TNBC) cells transfer cAMP through gap junctions, activating lipolysis in tumour-associated adipocytes to promote TNBC growth.

Adipose tissue responds to a variety of hormonal and environmental cues with changes in size, cellular composition and metabolic activity. Here Kajimura and Chouchani review our current understanding of adipocyte metabolism in physiology and metabolic disease, and they discuss strategies to reprogram adipocyte fate and metabolism.

Cardiovascular risks of cold exposure and the subsequent activation of the β3-AR pathway limit the application of beige fat thermogenesis for the treatment of obesity. Here, the authors show that optogenetics light-activated Ca2+ cycling in adipocytes triggers a fat-specific “cold-mimetic” thermogenesis response protecting mice against diet-induced obesity.

Tajima and colleagues identify mitochondrial lipoylation as a post-transcriptional molecular signature of aged brown adipose tissue (BAT) in mice. Reduced mitochondrial lipoylation is tightly coupled with the age-associated decline in BAT function, whereas enhanced lipoylation restores BAT activity in aged mice.

PPARγ ligands are used to control diabetes, but their anti-diabetic actions are puzzling. Here the authors show that phosphorylation of PPARγ by cyclin-dependent kinase 5 (Cdk5) in mice is linked to obesity induced by high-fat feeding, and that inhibition of the effect in humans by the drug rosiglitazone is closely associated with its anti-diabetic effects. Several anti-diabetic PPARγ ligands directly inhibit the effect, and thus support a more normal non-diabetic pattern of gene expression.

Inhibiting Notch signaling induces adipose browning, improves systemic glucose tolerance and insulin sensitivity, and suppresses weight gain in mice.

Modulating mitochondrial NAD⁺ levels by changing the expression of the mitochondrial NAD⁺ transporter, SLC25A51, Mukherjee et al. demonstrate that mitochondrial, rather than cytosolic or nuclear, NAD⁺ levels are a key determinant of the rate of liver regeneration.

The solute carrier transporter protein SLC25A44 regulates uptake of branched-chain amino acids in mitochondria of brown adipose tissue in which they are utilized for thermogenesis.

Beige fat serves as a substantial metabolic sink that dissipates energy and has consequently attracted much attention as a target for improving metabolic health. A recent study has provided a new molecular target, the N-terminal acetyltransferase Naa10p, for harnessing beige-fat biogenesis and improving whole-body energy homeostasis¹.

Calcium cycling induced by the SERCA2b–RyR2 pathway in beige fat cells allows for thermogenic activity independent of UCP1.

Latorre-Muro et al. show that the cytosolic chaperone PPID drives insertion of the mitochondrial import receptor TOM70 into the mitochondrial outer membrane, thereby regulating body temperature, glucose homeostasis and body weight in obese mice.

Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Here, the authors show that Sortilin in adipose tissues facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation, which controls adipose tissue fatty acid oxidation and substrate fuel selection during beige fat activation.

During fasting, hepatocytes selectively remodel the translatome while global translation is downregulated, showing a new signalling property of fatty acids and that, on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth.

We find that, relative to central neuropeptide Y, peripheral neuropeptide Y produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.

Chlorpyrifos is a widely-used pesticide and a common residue on vegetables and fruits. Here the authors show that at non-neurotoxic doses, chlorpyrifos reduces energy expenditure, by inhibiting diet induced thermogenesis, and promotes obesity and insulin resistance.

Trypanosome brucei is known to colonise the subcutaneous white adipose tissue and the interaction with the cellular locale could play key roles in pathogenesis and host response. Here the author’s use single cell approaches and in vivo animal models, and show a role for IL-17 in the adipose tissue response and parasite burden in a chronic murine model of infection.

The ubiquitin E3 ligase CUL2–APPBP2 determines PRDM16 protein stability by catalysing PRDM16 polyubiquitination in beige fat.

Sirtuins have been reported to positively regulate brown adipose tissue thermogenesis. Here the authors report that brown adipocytic SIRT7 suppresses whole-body energy expenditure and thermogenesis in mice, potentially by attenuating batokine gene expressions and Ucp1 mRNA translation.

The cap-binding protein eIF4E is a master regulator of mRNA translation. Conn et al. identify a specific subset of mRNAs governing lipid metabolism and storage that require eIF4E for translation in the liver during obesity.

Systemic modulation of branched-chain keto acid (BCKA) metabolism alters cardiac health. Here, the authors define the major fates of BCKA in the heart and demonstrate that acute exposure to BCKA levels found in obesity activates cardiac protein synthesis and markedly alters the heart phosphoproteome.

Thermogenic adipose tissue is a metabolic sink for excess fuel and is a promising target for the treatment of obesity and type 2 diabetes mellitus. However, hurdles exist in activating thermogenic adipose tissue in humans. A new study developed a drug screening platform utilizing human beige adipose tissue and identified non-canonical activators.

Embryonic, brown adipocytes, together with beige, brown-like adipocytes induced in white fat depots in response to various stimuli, constitute specialized heat-producing fat cells that contribute to organismal energy expenditure. Important insights have now been gained into the transcriptional and epigenetic regulation of biogenesis and thermogenesis of these cells, opening up new possibilities for the treatment of metabolic disorders.

The neurotransmitter serotonin has both central and peripheral effects. Here, the authors show that adipocyte-derived serotonin regulates organismal energy homeostasis in mice by acting on adipocyte serotonin receptors on fat cells, which regulates lipolysis and thermogenesis in white and brown fat tissue.

Demethylase JMJD1A activates thermogenesis-related target genes in response to β-adrenergic hormones. Here, the authors show that phosphorylation of JMJD1A at S265 increases its interaction with the SWI/SNF chromatin remodeler, leading to long-range chromatin interactions and target gene activation.

In mice, expression of PGC1-α in muscles is shown to stimulate expression of FNDC5, which is cleaved and secreted in the circulation as the newly identified hormone irisin; on exercise, this hormone stimulates browning of subcutaneous adipose tissue.

Harnessing the thermogenic, energy-expending capacity of adipocytes has the potential to combat metabolic disorders. Although β₃-adrenergic receptor agonists are the best-known activators of thermogenesis, they carry considerable cardiovascular risks. A new study demonstrates the ability of G protein-coupled receptor 3 to intrinsically drive adipose thermogenesis independent of β₃-adrenergic receptor signalling.

JMJD1A is essential for thermogenic gene induction in brown adipose tissue. Here the authors show that white adipose tissue beige-ing requires both β-adrenergic-dependent phosphorylation of S265 and demethylation activity of JMJD1A while brown adipose tissue-driven thermogenesis requires β-adrenergic dependent phosphorylation of S265 but is independent of H3K9me2 demethylation.

This broad group of authors summarizes the impact of circadian factors on metabolic biology and offers recommendations on how to account for and report biological, environmental and experimental factors affecting circadian rhythms in metabolic studies in rodents.

A comparative metabolomics approach is used to identify succinate as a key activator of thermogenesis in brown adipose tissue.

Here it is shown that PRDM16, a zinc finger protein that controls the switch from myoblastic precursors to brown fat cells, works together with C/EBP-β and that expression of this transcriptional unit is sufficient to induce a fully functional brown fat program in naive fibroblasts. Transplantation of such fibroblasts into mice creates a brown fat pad that acts as a sink for glucose.

In the triple-negative subtype of breast cancer, for which treatment options are limited, overexpression of the MYC oncoprotein is associated with increased sensitivity to growth inhibition by fatty acid oxidation inhibitors, thus pointing to a new therapeutic strategy.

Brown adipose tissue-enriched lysine methyltransferase EHMT1 is an essential enzyme in the PRDM16–C/EBP-β transcriptional complex that controls brown adipose cell fate and energy metabolism.

Clonally-derived cell lines of human preadipocytes from BAT biopsies allows for the genetic and functional characterization of adipocytes from this tissue

Brown and beige adipocytes are mammalian thermogenic fat cells that regulate whole-body energy metabolism. Notably, brown/beige adipocytes are heterogeneous and their functions extend beyond thermogenesis, encompassing roles as metabolite sinks, as secretory cells and as regulators of adipose tissue homeostasis. Thus, induction of brown/beige fat activity correlates with improved metabolic health.