Nonalcoholic steatohepatitis (NASH) is characterized by progressive liver injury, inflammation, and fibrosis; however, the mechanisms that govern the transition from hepatic steatosis, which is relatively benign, to NASH remain poorly defined. Neuregulin 4 (Nrg4) is an adipose tissue–enriched endocrine factor that elicits beneficial metabolic effects in obesity. Here, we show that Nrg4 is a key component of an endocrine checkpoint that preserves hepatocyte health and counters diet-induced NASH in mice. Nrg4 deficiency accelerated liver injury, fibrosis, inflammation, and cell death in a mouse model of NASH. In contrast, transgenic expression of Nrg4 in adipose tissue alleviated diet-induced NASH. Nrg4 attenuated hepatocyte death in a cell-autonomous manner by blocking ubiquitination and proteasomal degradation of c-FLIP_L, a negative regulator of cell death. Adeno-associated virus–mediated (AAV-mediated) rescue of hepatic c-FLIP_L expression in Nrg4-deficent mice functionally restored the brake for steatosis to NASH transition. Thus, hepatic Nrg4 signaling serves as an endocrine checkpoint for steatosis-to-NASH progression by activating a cytoprotective pathway to counter stress-induced liver injury.

Significance: Brown and beige fat function has important implications for metabolic physiology and the treatment of metabolic disorders. How transcription factors interface with long noncoding RNAs (lncRNAs), an emerging class of regulatory factors, to drive development and thermogenesis of brown/beige fat remains essentially unknown. Here we identified Zbtb7b as an activator of the thermogenic gene program through a genome-wide functional screen and showed that it plays an essential role in cold-induced thermogenesis and beige fat formation. Mechanistically, Zbtb7b forms a ribonucleoprotein transcriptional complex with the lncRNA Blnc1 and drives thermogenic gene expression via a feedforward loop. This work illustrates the emerging concept of a protein–lncRNA regulatory network in the control of adipose tissue biology and energy metabolism.

Persistent inflammation disrupts functional recovery after spinal cord injury (SCI). Peroxisome proliferator-activated receptor gamma (PPAR-γ) activation promotes functional recovery in SCI rats by inhibiting inflammatory cascades and increasing neuronal survival. We sought to clarify the relationship between PPAR-γ activation and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome suppression, and the role of NF-κB in activating the NLRP3 inflammasome in neurons. In SCI rats, we found that rosiglitazone (PPAR-γ agonist) inhibited the expression of caspase-1. In in vitro neurons, G3335 (PPAR-γ antagonist) reversed the rosiglitazone-induced inhibition of caspase-1, interleukin 1 (IL-1β), and interleukin 6 (IL-6). Rosiglitazone inhibited the expression of NLRP3, caspase-1, IL-1β, and IL-6. However, the activator of NLRP3 could counteract this inhibition induced by PPAR-γ activation. NF-κB did not participate in the process of rosiglitazone-induced inhibition of NLRP3. Consistent with our in vitro results, we verified that locomotor recovery of SCI rats in vivo was regulated via PPAR-γ, NLRP3, and NF-κB. These results suggest that PPAR-γ activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome—but not NF-κB—in neurons and that PPAR-γ activation is a promising therapeutic target for SCI.

Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat–enriched secreted factor NRG4 protects mice from high-fat diet–induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake.

Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we show that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensable role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility at PPARγ and EBF2 binding sites for key thermogenic genes. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced cold-induced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis.

Background/Aims: Both physiologic remodeling and pathologic regeneration of cartilage tissue rely upon chondrocyte functions and are benefited from factors that promote viability and inhibit apoptosis of the cell, and associated mechanisms. High level of reactive oxygen species (ROS) and proinflammatory cytokines activate apoptosis signaling and initiate cell death, which can be attenuated by antioxidants. This study examined the effect of catalase (CAT) on ROS and tumor necrosis factor-α (TNF-α)-induced apoptosis in human C28/I2 chondrocytes cultured in monolayer. Methods: Chondrocytes were treated with diluted CAT in the presence or absence of TNF-α and compared to untreated cells. Levels of hydrogen peroxide (H₂O₂) and mitochondrial membrane potential (Δψ_m) were measured using fluorescent labeling, cell apoptosis was assayed by flow cytometry using Annexin V/propidium iodide (PI) staining, gene expression was detected by quantitative real time polymerase chain reaction (qRT-PCR) and the proteins were investigated by Western blotting. Results: CAT effectively reduced the intracellular ROS caused by the monolayer culture system, enhanced the Δψ_m depending on the presence of TNF-α and promoted morphological features at sub-cellular level. CAT also attenuated the TNF-α-upregulated expression of factors/mediators of extrinsic cell death cascade and apoptotic caspases, ultimately resulted in promoted cellular viability. Conclusion: The anti-apoptotic effect of CAT on chondrocytes via scavenging ROS and suppressing TNF-α-induced cell apoptosis by TNF/TNF receptor (TNFR) mediated death signaling pathway and potentiate CAT as a complementary agent beneficial to cartilage remodeling and regeneration in vivo, and cell-based therapies of cartilage repair demanding viable cells expanded ex vivo.