Recent Advances in Adipose Tissue Dysfunction and Its Role in the Pathogenesis of Non-Alcoholic Fatty Liver Disease

Obesity is a serious ongoing health problem that significantly increases the incidence of nonalcoholic fatty liver disease (NAFLD). During obesity, adipose tissue dysfunction is obvious and characterized by increased fat deposition (adiposity) and chronic low-grade inflammation. The latter has been implicated to critically promote the development and progression of NAFLD, whose advanced form non-alcoholic steatohepatitis (NASH) is considered one of the most common causes of terminal liver diseases. This review summarizes the current knowledge on obesity-related adipose dysfunction and its roles in the pathogenesis of hepatic steatosis and inflammation, as well as liver fibrosis. A better understanding of the crosstalk between adipose tissue and liver under obesity is essential for the development of new and improved preventive and/or therapeutic approaches for managing NAFLD.

Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis

It has been previously shown that chronic ethanol administration-induced increase in adipose tissue lipolysis and reduction in the secretion of protective adipokines collectively contribute to alcohol-associated liver disease (ALD) pathogenesis. Further studies have revealed that increased adipose S-adenosylhomocysteine (SAH) levels generate methylation defects that promote lipolysis. Here, we hypothesized that increased intracellular SAH alone causes additional related pathological changes in adipose tissue as seen with alcohol administration. To test this, we used 3-deazaadenosine (DZA), which selectively elevates intracellular SAH levels by blocking its hydrolysis. Fully differentiated 3T3-L1 adipocytes were treated in vitro for 48 h with DZA and analysed for lipolysis, adipokine release and differentiation status. DZA treatment enhanced adipocyte lipolysis, as judged by lower levels of intracellular triglycerides, reduced lipid droplet sizes and higher levels of glycerol and free fatty acids released into the culture medium. These findings coincided with activation of both adipose triglyceride lipase and hormone sensitive lipase. DZA treatment also significantly reduced adipocyte differentiation factors, impaired adiponectin and leptin secretion but increased release of pro-inflammatory cytokines, IL-6, TNF and MCP-1. Together, our results demonstrate that elevation of intracellular SAH alone by DZA treatment of 3T3-L1 adipocytes induces lipolysis and dysregulates adipokine secretion. Selective elevation of intracellular SAH by DZA treatment mimics ethanol’s effects and induces adipose dysfunction. We conclude that alcohol-induced elevations in adipose SAH levels contribute to the pathogenesis and progression of ALD.

Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction

Emerging evidence highlights that dysfunction of adipose tissue contributes to impaired insulin sensitivity and systemic metabolic deterioration in obese state. Of note, adipocyte hypertrophy serves as a critical event which associates closely with adipose dysfunction. An increase in cell size exacerbates hypoxia and inflammation as well as excessive collagen deposition, finally leading to metabolic dysregulation. Specific mechanisms of adipocyte hypertrophy include dysregulated differentiation and maturation of preadipocytes, enlargement of lipid droplets, and abnormal adipocyte osmolarity sensors. Also, weight loss therapies exert profound influence on adipocyte size. Here, we summarize the critical role of adipocyte hypertrophy in the development of metabolic disturbances. Future studies are required to establish a standard criterion of size measurement to better clarify the impact of adipocyte hypertrophy on changes in metabolic homeostasis.

Altered Regulation of adipomiR Editing with Aging

Adipose dysfunction with aging increases risk to insulin resistance and other chronic metabolic diseases. We previously showed functional changes in microRNAs involved in pre-adipocyte differentiation with aging resulting in adipose dysfunction. However, the mechanisms leading to this dysfunction in microRNAs in adipose tissue (adipomiRs) during aging are not well understood. We determined the longitudinal changes in expression of adipomiRs and studied their regulatory mechanisms, such as miRNA biogenesis and editing, in an aging rodent model, with Fischer344 × Brown-Norway hybrid rats at ages ranging from 3 to 30 months (male/females, n > 8). Expression of adipomiRs and their edited forms were determined by small-RNA sequencing. RT-qPCR was used to measure the mRNA expression of biogenesis and editing enzymes. Sanger sequencing was used to validate editing with aging. Differential expression of adipomiRs involved in adipocyte differentiation and insulin signaling was altered with aging. Sex- and age-specific changes in edited adipomiRs were observed. An increase in miRNA biogenesis and editing enzymes (ADARs and their splice variants) were observed with increasing age, more so in female than male rats. The adipose dysfunction observed with age is attributed to differences in editing of adipomiRs, suggesting a novel regulatory pathway in aging.

NLRP3 Inflammasome in Inflammation and Metabolism: Identifying Novel Roles in Postburn Adipose Dysfunction

Inflammasomes are multiprotein complexes that respond to pathogen or host associated damage markers, leading to caspase-1 maturation and processing of pro-inflammatory cytokines. Initially, inflammasomes were implicated primarily in inflammatory and infectious conditions. However, increasing evidence demonstrates broader roles beyond inflammation, including regulation of adipose tissue metabolism after burns. Here, we conducted a search for articles on PubMed, Web of Science, Embase, Scopus, and UpToDate with applied search strategies including a combination of “burns,” “trauma,” “(NLRP3) inflammasome,” “metabolic conditions,” “white adipose tissue,” “macrophages,” “browning,” and “lipolysis” and included papers from 2000 to 2020. We discuss unexpected roles for NLRP3, the most characterized inflammasome to date, as a key metabolic driver in a variety of conditions. In particular, we highlight the function of NLRP3 inflammasome in burn trauma, which is characterized by both hyperinflammation and hypermetabolism. We identify a critical part for NLRP3 activation in macrophage dynamics and delineate a novel role in postburn white adipose tissue remodeling, a pathological response associated with hypermetabolism and poor clinical outcomes. Mechanistically, how inflammation and inflammasome activation is linked to postburn hypermetabolism is a novel concept to contemplate, and herein we provide evidence of an immunometabolic crosstalk between adipocytes and infiltrating macrophages.

L-glutamine ameliorates adipose-hepatic dysmetabolism in OC-treated female rats

Adipose dysfunction and inflammation with or without hepatic defects underlie metabolic obesity. Glutamine (GLU) improves glucoregulation and metabolic indices but its effects on adipose function and hepatic lipid deposition in estrogen-progestin oral contraceptive (EPOC) users are unknown. Therefore, we hypothesized that GLUT supplementation would protect against adipose dysfunction and excess hepatic lipid influx and deposition in EPOC-treated animals by suppressing adenosine deaminase/xanthine oxidase (ADA/XO) activity and improving glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant defense. Female Wistar rats weighing 150–180 g were allotted into control, GLUT, EPOC and EPOC + GLUT groups (six rats/group). The groups received vehicle (distilled water, p.o.), GLUT (1 g/kg), EPOC containing 1.0 µg ethinylestradiol plus 5.0 µg levonorgestrel and EPOC plus GLUT, respectively, daily for 8 weeks. Results showed that the administration of EPOC caused glucose dysregulation and increased triglyceride-glucose index and visceral adiposity, but the body weight and liver weight were not affected. However, EPOC significantly decreased adipose lipid, G6PD and glutathione and increased glycogen synthesis, ADA, XO, uric acid, lipid peroxidation, lactate production and gamma-glutamyl transferase activity (GGT). On the other hand, EPOC increased hepatic lipid, ADA, XO, uric acid, lipid peroxidation and lactate production and decreased glycogen synthesis, G6PD and glutathione. Nevertheless, supplementation with glutamine attenuated these alterations. Collectively, the present results indicate that EPOC causes metabolically induced obesity which is associated with adipose dysfunction and hepatic metabolic disturbance. The findings also suggest that glutamine confers metabo-protection with corresponding improvement in adipose and hepatic metabolic function by suppression of ADA/XO activity and enhancement of G6PD-dependent antioxidant defense.