Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice

Abstract

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

Mfn2 is critical for brown adipose tissue thermogenic function

“…Our results support the view that reduced BAT thermogenic function and oxidative capacity in adipose tissues can also be beneficial for overall insulin sensitivity in certain scenarios, such as those allowing for improved adipose tissue expandability. Our results are in line with recent evidence from mouse models for adipose‐specific impairments in fatty acid catabolism, either through the deletion of the adipose triglyceride lipase (ATGL) (Schoiswohl et al , 2015), the TCA cycle enzyme fumarate hydratase (Yang et al , 2016), or the epigenetic regulator lysine‐specific demethylase 1 (Lsd1) (Duteil et al , 2016), all of which displayed impaired thermogenesis yet prevention against diet‐induced insulin resistance. Nevertheless, there is a remarkable variability on how the genetic ablation of mitochondrial proteins specifically in adipose tissues influences diet‐induced metabolic damage (Vernochet et al , 2014; Lee et al , 2015), likely reflecting the different impacts of these genes on the multiple functions of adipose tissue mitochondria beyond thermogenesis.…”

Liver X receptor α mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression

“…In WT mice, fasting increased hepatic mRNA expression of G0S2 by 8.3-fold and ATGL by 2.3-fold ( Figure 1A), indicating a relatively greater effect on G0S2. To determine the contribution of adipocyte lipolysis to the fasting-induced upregulation in liver, we next compared their expression in adipocyte-specific ATGL KO (AAKO) mice that have previously been shown to have severely restricted adipocyte lipolysis (36). In the fasted AAKO mice, mRNA expression of G0S2 was 9.1-fold lower and ATGL was 6.58-fold higher than in the WT mice ( Figure 1B).…”

“…These mice were subsequently used for adipose tissue excision and explant culture. Adipose-specific ATGL KO mice (AAKO) were produced as previously described (36). For experimental analysis, male AAKO mice and age-matched WT littermates at 24 weeks of age were used.…”

Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis

“…6, F to H). Acute triglyceride lipolysis induces transient inflammation in adipose tissue (38)(39)(40)(41). Therefore, we examined the effect of adipocyte-specific genetic inactivation of the adipose triglyceride lipase (ATGL) on Jak-Stat3-Tgfb3 regulation.…”