Ekaterina D. Korobkina

Non-shivering thermogenesis by brown adipose tissue (BAT) is a promising target for anti-obesity therapies, making its regulatory mechanisms of significant translational interest. While cold-induced BAT thermogenesis (CIT) is well characterized, certain high-calorie diets can also activate BAT in the absence of cold, a process known as diet-induced thermogenesis (DIT). Despite its potential relevance to modern human diets and lifestyles, the mechanisms and physiological relevance underlying DIT remain poorly understood. Here, we show that DIT reduces adiposity and protects against hepatic steatosis and fibrosis in males but not female mice. Moreover, adipose tissue-specific ablation of uncoupling protein 1 (UCP1) reveals that BAT is the primary mediator of DIT but that non-adipocyte UCP1 also contributes to body weight regulation. Transcriptome analysis suggests that DIT is triggered by intrinsic metabolic stress, distinguishing it from CIT, which is driven by sympathetic tone. Finally, BAT-specific arteriovenous metabolomics identifies glucose as the predominant circulating fuel for DIT. These findings uncover distinct molecular and metabolic features of DIT, highlighting opportunities to harness BAT activity for treating obesity and metabolic diseases without requiring cold exposure.

Aberrant mTORC1 activation in renal tubular epithelial cells (rTECs) is implicated as a critical driver of renal cystic diseases (RCDs), including autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis (TSC), yet its precise role remains unclear. Rag GTPases recruit mTORC1 to lysosomes, its intracellular activation site. Unexpectedly, we found that deleting RagA/B in rTECs, despite inhibiting mTORC1, triggers renal cystogenesis and kidney failure. We identify TFEB as the key driver of cystogenesis downstream of RagA/B loss and show that Rag GTPases, rather than mTORC1, are the primary suppressors of TFEB in vivo . We further highlight increased nuclear TFEB as a shared feature of several RCD models, whereas differences in mTORC1 activity may explain the variable efficacy of mTORC1 inhibitors. Finally, we provide evidence that nuclear TFEB, rather than mTORC1 activation, is a more consistent biomarker of cyst-lining epithelial cells in ADPKD. Overall, these findings challenge the prevailing view that mTORC1 hyperactivation is required for renal cystogenesis, which has important translational implications. Teaser: A serendipitous finding uncovers the Rag GTPases as strong suppressors of renal cystogenesis with important disease implications.

Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT.

Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating metabolite exchange remains unclear. Here, we quantified metabolite exchange in BAT and skeletal muscle by arteriovenous metabolomics during cold exposure in fed male mice. This identified unexpected metabolites consumed, released and shared between organs. Quantitative analysis of tissue fluxes showed that glucose and lactate provide ~85% of carbon for adaptive thermogenesis and that cold and CL316,243 trigger markedly divergent fuel utilization profiles. In cold adaptation, BAT also dramatically increases nitrogen uptake by net consuming amino acids, except glutamine. Isotope tracing and functional studies suggest glutamine catabolism concurrent with synthesis via glutamine synthetase, which avoids ammonia buildup and boosts fuel oxidation. These data underscore the ability of BAT to function as a glucose and amino acid sink and provide a quantitative and comprehensive landscape of BAT fuel utilization to guide translational studies.