AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms ...that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK β regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK.
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► GSK3 constitutively interacts with the AMPK complex through the β subunit ► GSK3 phosphorylates the α subunit of AMPK and inhibits its kinase activity ► The PI3K-Akt pathway enhances GSK3-dependent phosphorylation of the α subunit ► GSK3-dependent AMPK inhibition is critical for cells to enter an anabolic state
Brown and beige/brite fats generate heat via uncoupled respiration to defend against cold. The total mass and activity of thermogenic adipose tissues are also tightly linked to systemic energy and ...nutrient homeostasis. Despite originating from distinct progenitors, brown and beige adipocytes acquire remarkably similar molecular and metabolic characteristics during differentiation through the action of a network of transcription factors and cofactors. How this regulatory network interfaces with long noncoding RNAs (lncRNAs), an emerging class of developmental regulators, remains largely unexplored. Here, we globally profiled lncRNA gene expression during thermogenic adipocyte formation and identified Brown fat lncRNA 1 (Blnc1) as a nuclear lncRNA that promotes brown and beige adipocyte differentiation and function. Blnc1 forms a ribonucleoprotein complex with transcription factor EBF2 to stimulate the thermogenic gene program. Further, Blnc1 itself is a target of EBF2, thereby forming a feedforward regulatory loop to drive adipogenesis toward thermogenic phenotype.
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•Blnc1 is a highly regulated lncRNA during thermogenic adipocyte development•Blnc1 drives the thermogenic gene program in brown and beige adipocytes•Blnc1 forms a ribonucleoprotein transcriptional complex with EBF2•Blnc1 and EBF2 are assembled into a feedforward regulatory loop
Brown and beige fat generate heat via uncoupled respiration. Zhao et al. globally profiled long noncoding RNAs (lncRNAs) and identified brown fat lncRNA 1 (Blnc1) as a nuclear lncRNA that promotes brown and beige adipocyte differentiation by forming a feedforward regulatory loop with EBF2 to drive adipogenesis toward a thermogenic phenotype.
Long noncoding RNAs (lncRNAs) are emerging as an integral part of the regulatory information encoded in the genome. lncRNAs possess the unique capability to interact with nucleic acids and proteins, ...and exert discrete effects on numerous biological processes. Recent studies have delineated multiple lncRNA pathways that control metabolic tissue development and function. The expansion of the regulatory code that links nutrient and hormonal signals to tissue metabolism gives new insights into the genetic and pathogenic mechanisms underlying metabolic disease. This review discusses lncRNA biology with a focus on their role in the development, signaling, and function of key metabolic tissues.
lncRNAs exhibit tissue-specific and highly regulated expression patterns, and are frequently dysregulated in disease states.
lncRNAs regulate diverse biological processes through the formation of lncRNA–protein and lncRNA–miRNA complexes to control gene expression and function.
lncRNAs regulate metabolic tissue development and function, including adipogenesis, hepatic lipid metabolism, islet function, and energy balance.
lncRNAs are important regulators of skeletal and cardiac muscle development, and of the immune response.
The last two decades have witnessed an explosion of interest in adipocyte biology, coinciding with the upsurge of obesity and metabolic syndrome. Now we have new perspectives on the distinct ...developmental origins of white, brown, and beige adipocytes and their role in metabolic physiology and disease. Beyond fuel metabolism, adipocytes communicate with the immune system and other tissues by releasing diverse paracrine and endocrine factors to orchestrate adipose tissue remodeling and maintain systemic homeostasis. Significant progress has been made in delineating the regulatory networks that govern different aspects of adipocyte biology. Here we provide an overview on the emerging role of long noncoding RNAs (lncRNAs) in the regulation of adipocyte development and metabolism and discuss the implications of the RNA-protein regulatory interface in metabolic control.
Nonalcoholic fatty liver disease (NAFLD), a spectrum of metabolic liver disease associated with obesity, ranges from relatively benign hepatic steatosis to nonalcoholic steatohepatitis (NASH). The ...latter is characterized by persistent liver injury, inflammation, and liver fibrosis, which collectively increase the risk for end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. Recent work has shed new light on the pathophysiology of NAFLD NASH, particularly the role of genetic, epigenetic, and dietary factors and metabolic dysfunctions in other tissues in driving excess hepatic fat accumulation and liver injury. In parallel, single-cell RNA sequencing studies have revealed unprecedented details of the molecular nature of liver cell heterogeneity, intrahepatic cross talk, and disease-associated reprogramming of the liver immune and stromal vascular microenvironment. This review covers the recent advances in these areas, the emerging concepts of NASH pathogenesis, and potential new therapeutic opportunities.
Exercise can improve cognitive function and has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation ...of this neurotrophin remain unknown. Here we show that FNDC5, a previously identified muscle protein that is induced in exercise and is cleaved and secreted as irisin, is also elevated by endurance exercise in the hippocampus of mice. Neuronal Fndc5 gene expression is regulated by PGC-1α, and Pgc1a−/− mice show reduced Fndc5 expression in the brain. Forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, whereas RNAi-mediated knockdown of FNDC5 reduces Bdnf. Importantly, peripheral delivery of FNDC5 to the liver via adenoviral vectors, resulting in elevated blood irisin, induces expression of Bdnf and other neuroprotective genes in the hippocampus. Taken together, our findings link endurance exercise and the important metabolic mediators, PGC-1α and FNDC5, with BDNF expression in the brain.
•Exercise induces FNDC5 in the hippocampus•PGC-1α regulates neuronal Fndc5 gene expression in vitro and in vivo•FNDC5 positively regulates the expression of the important neurotrophin BDNF•Peripheral delivery of FNDC5 via adenoviral vectors induces Bdnf in the hippocampus
Temporal organization of tissue metabolism is important for maintaining nutrient and energy homeostasis in mammals. Autophagy is a conserved cellular pathway that is activated in response to nutrient ...limitation, resulting in the degradation of cytoplasmic components and the release of amino acids and other nutrients. Here, we show that autophagy exhibits robust circadian rhythm in mouse liver, which is accompanied by cyclic induction of genes involved in various steps of autophagy. Functional analyses of transcription factors and cofactors identified C/EBPβ as a potent activator of autophagy. C/EBPβ is rhythmically expressed in the liver and is regulated by both circadian and nutritional signals. In cultured primary hepatocytes, C/EBPβ stimulates the program of autophagy gene expression and is sufficient to activate autophagic protein degradation. Adenoviral‐mediated RNAi knockdown of C/EBPβ in vivo abolishes diurnal autophagy rhythm in the liver. Further, circadian regulation of C/EBPβ and autophagy is disrupted in mice lacking a functional liver clock. We have thus identified C/EBPβ as a key factor that links autophagy to biological clock and maintains nutrient homeostasis throughout light/dark cycles.
This study reveals that C/EBPβ expression is regulated by the circadian clock and feeding/fasting rhythms. C/EBPβ regulates the transcription of autophagy‐related genes and its circadian expression underlies the rhythmic regulation of autophagy in mouse liver.
Highlights • Brown fat contributes to systemic metabolism via thermogenesis-dependent and -independent mechanisms. • The brown fat secretome incudes Nrg4, FGF21, and BMPs, among others. • The brown ...fat secretome may coordinate metabolic adaptation during thermogenesis. • Developing novel therapies based on brown fat thermogenesis may target the extracellular factors released by brown fat.
Chronic disruption of energy balance, where energy intake exceeds expenditure, is a major risk factor for the development of metabolic syndrome. The latter is characterized by a constellation of ...symptoms including obesity, dyslipidemia, insulin resistance, hypertension, and nonalcoholic fatty liver disease. Altered expression of genes involved in glucose and lipid metabolism as well as mitochondrial oxidative phosphorylation has been implicated in the pathogenesis of these disorders. The peroxisome proliferator-activated receptor T coactivator-1 （PGC-1） family of transcriptional coactivators is emerging as a hub linking nutritional and hormonal signals and energy metabolism. PGC-loL and PGC-I3 are highly responsive to environmental cues and coordinate metabolic gene programs through interaction with transcription factors and chromatin-remodeling proteins. PGC-loL has been implicated in the pathogenic conditions including obesity, type 2 diabetes, neurodegeneration, and cardiomyopathy, whereas PGC-1β plays an important role in plasma lipoprotein homeostasis and serves as a hepatic target for niacin, a potent hypotriglyeeridemic drug. Here, we review recent advances in the identification of physiological and pathophysiological contexts involving PGC-1 coactivators, and also discuss their implications for therapeutic development.
Hepatic lipogenesis is aberrantly induced in nonalcoholic fatty liver disease (NAFLD) via activation of the LXR-SREBP1c pathway. To date, a number of protein factors impinging on the transcriptional ...activity of LXR and SREBP1c have been elucidated. However, whether this regulatory axis interfaces with long noncoding RNAs (lncRNAs) remains largely unexplored. Here we show that hepatic expression of the lncRNA Blnc1 is strongly elevated in obesity and NAFLD in mice. Blnc1 is required for the induction of SREBP1c and hepatic lipogenic genes in response to LXR activation. Liver-specific inactivation of Blnc1 abrogates high-fat diet-induced hepatic steatosis and insulin resistance and protects mice from diet-induced nonalcoholic steatohepatitis. Proteomic analysis of the Blnc1 ribonucleoprotein complex identified EDF1 as a component of the LXR transcriptional complex that acts in concert with Blnc1 to activate the lipogenic gene program. These findings illustrate a lncRNA transcriptional checkpoint that licenses excess hepatic lipogenesis to exacerbate insulin resistance and NAFLD.
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