The prevalence of obesity has led to a surge of interest in understanding the detailed mechanisms underlying adipocyte development. Many protein-coding genes, mRNAs, and microRNAs have been implicated in adipocyte development, but the global expression patterns and functional contributions of long noncoding RNA (lncRNA) during adipogenesis have not been explored. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis.

SUMMARY Mitochondria undergo architectural/functional changes in response to metabolic inputs. How this process is regulated in physiological feeding/fasting states remains unclear. Here we show that mitochondrial dynamics (notably fission and mitophagy) and biogenesis are transcriptional targets of the circadian regulator Bmal1 in mouse liver and exhibit a metabolic rhythm in sync with diurnal bioenergetic demands. Bmal1 loss-of-function causes swollen mitochondria incapable of adapting to different nutrient conditions accompanied by diminished respiration and elevated oxidative stress. Consequently, liver-specific Bmal1 knockout (LBmal1KO) mice accumulate oxidative damage and develop hepatic insulin resistance. Restoration of hepatic Bmal1 activities in high fat fed mice improves metabolic outcomes, whereas expression of Fis1, a fission protein that promotes quality control rescues morphological/metabolic defects of LBmal1KO mitochondria. Interestingly, Bmal1 homologue AHA-1 in C. elegans retains the ability to modulate oxidative metabolism and lifespan despite lacking circadian regulation. These results suggest clock genes are evolutionarily conserved energetics regulators.

Mammals have two principal types of fat. White adipose tissue (WAT) primarily serves to store extra energy as triglycerides, while brown adipose tissue (BAT) is specialized to burn lipids for heat generation and energy expenditure as a defense against cold and obesity 1, 2. Recent studies demonstrate that brown adipocytes arise in vivo from a Myf5-positive, myoblastic progenitor by the action of Prdm16 (PR domain containing 16). Here, we identified a brown fat-enriched miRNA cluster, miR-193b-365, as a key regulator of brown fat development. Blocking miR-193b and/or miR-365 in primary brown preadipocytes dramatically impaired brown adipocyte adipogenesis by enhancing Runx1t1 (runt-related transcription factor 1; translocated to, 1) expression whereas myogenic markers were significantly induced. Forced expression of miR-193b and/or miR-365 in C2C12 myoblasts blocked the entire program of myogenesis, and, in adipogenic condition, miR-193b induced myoblasts to differentiate into brown adipocytes. MiR-193b-365 was upregulated by Prdm16 partially through Pparα. Our results demonstrate that miR-193b-365 serves as an essential regulator for brown fat differentiation, in part by repressing myogenesis.

Introduction Obesity and obesity-related disease have reached pandemic proportions and are prevalent even in developing countries. Adipose tissue is increasingly being recognized as a key regulator of whole-body energy homeostasis and consequently as a prime therapeutic target for metabolic syndrome. This review discusses the roles of miRNAs, small endogenously expressed RNAs that regulate gene expression at a post-transcriptional level, in the development and function of adipose tissue and other relevant metabolic tissues impacted by obesity. Several high-throughput studies have identified hundreds of miRNAs that are differentially expressed during the development of metabolic tissues or as an indication of pathophysiology. Further investigation has functionalized the regulatory capacity of individual miRNAs and revealed putative targets for these miRNAs. Therefore, as with several other pathologies, miRNAs are emerging as feasible therapeutic targets for metabolic syndrome. Areas covered This review provides a comprehensive view of miRNAs involved in adipogenesis, from mesenchymal stem cell lineage determination through terminal adipocyte differentiation. We also discuss the differential expression of miRNAs among adipose depots and the dysregulation of miRNAs in other metabolic tissues during metabolic pathophysiology. Finally, we discuss the therapeutic potential of targeting miRNAs in obesity and give a perspective on the challenges and advantages of miRNA-based drugs. Expert opinion miRNAs are extensive regulators of adipocyte development and function and are viable therapeutic targets for obesity. Despite the broad-spectrum and redundancy of miRNA–target interactions, sophisticated bioinformatic approaches are making it possible to determine the most physiologically relevant miRNAs to target in disease. In vivo delivery of miRNAs for therapeutic purposes is rapidly developing and has been successful in other contexts. Additionally, miRNAs can be used as prognosis markers for disease onset and progression. Ultimately, miRNAs are prime therapeutic targets for obesity and its consequent pathologies in other metabolic tissues.

Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.