Adiponectin synthesis and secretion by subcutaneous adipose tissue is impaired during obesity by endoplasmic reticulum stress

Abstract

Subcutaneous (SAT) and visceral (VAT) adipose tissues stores excess energy as triglycerides and synthesize adiponectin to prevent ectopic lipid accumulation and lipotoxicity. During obesity, an impairment in the capacity of SAT to store triglycerides and synthesize adiponectin is associated with increased free fatty acids (FFA) release, leading to VAT hypertrophy and hepatic and skeletal muscle lipotoxicity. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may be involved in SAT dysfunction during obesity. The objectives of this study were to assess UPR activation and adiponectin synthesis in: 1) SAT and VAT from mice exposed to acute pharmacologic or chronic obesity-induced ER stress and in 2) cultured mice primary mature adipocytes or adipocytes differentiated in vitro from SAT and VAT exposed to tunicamycin or thapsigargin. Mice fed a high-fat diet developed obesity, increased FFA and lower circulating adiponectin in association with lower adiponectin synthesis and increased UPR markers in SAT. Mice subjected to acute ER stress by pioglitazone administration and a low-dose tunicamycin injection presented a maladaptive UPR activation in SAT along with reduced adiponectin synthesis and secretion and increased lipolysis with respect to VAT, associated with lipid accumulation in skeletal muscle and liver. Primary adipocytes and adipocytes differentiated from SAT exposed to pharmacologic ER stress also developed maladaptive UPR, along with reduced adiponectin synthesis and increased lipolysis with respect to those from VAT. Our results indicate that compared to VAT, SAT is more susceptible to ER stress, leading to increased lipolysis and reduced adiponectin synthesis and secretion.

Dysfunctional Adiposity Index as a Useful Clinical Tool for Early Identification of Adipose Tissue Morpho-Functional Abnormalities and Cardiometabolic Disorders in Apparently Healthy Subjects

“…[22,30] On the other hand, reduced adipocytes cell number along with enlarged size have been considered morphological indicators of hypertrophic adipocytes that play a role in obesity-related cardiovascular and metabolic abnormalities. [15][16][17] Data of the present study indicates that ALR signi cantly correlates with subcutaneous adipocytes number (r = 0.525; p = 0.001) and area (r = -0.431; p = 0.009), as well as with the relation of area/number of adipocytes (r = -0.529; p = 0.001) as indicator of morphologically abnormal adipocytes. Moreover, Figure 2 shows that the simple DAI equation was strongly correlated with morpho-functional alterations in adipose tissue.…”

“…When the storage capacity of SAT is exceeded or its ability to generate new adipocytes is impaired, TG begins to accumulate in tissues outside the SAT, such as VAT, skeletal muscle, and liver. [15,38] Thus, it can be hypothesized that in the progression of cardiometabolic alterations, the earlier stages of adipose tissue dysfunction comprise the impairment in SAT expansion and activation of in ammatory macrophages, re ected by low number of adipocytes, hypertrophy, and the presence of low-grade systemic in ammation (MCP-1, IL-1 , and hs-CRP). The increased fatty acids release in a later stage lead to ectopic fat accumulation and progression to severe metabolic derangements in more advanced stages ( Figure 6).…”

“…[12][13][14] Adipose tissue dysfunction is a multi-step process where in early stages subcutaneous adipose tissue (SAT) fail to appropriately store energy, resulting in enlarged adipocytes (hypertrophic) that promotes systemic low-grade in ammation and fat deposition in visceral adipose tissue (VAT). [15] At later stages hypoxia, adipocyte pyrpoptosis, and in ammatory macrophage recruitment increases subcutaneous and visceral AT dysfunction that lead to increases ectopic fat deposition in liver and skeletal muscle, as well as to lipotoxicity, insulin resistance and impaired systemic metabolism. [16,17] Considering that 10-40% of subjects with normal body weight have been identi ed with metabolic abnormalities, and 20-30% of those with BMI ≥ 25 kg/m 2 appear to be metabolically healthy, several clinical markers have been proposed as subrogated to AT functionality in order to easily identifying cardiometabolic abnormalities.…”

Endoplasmic reticulum stress and development of insulin resistance in adipose, skeletal, liver, and foetoplacental tissue in diabesity

“…Induction of ER stress in human adipocytes in vitro reduces adiponectin expression (Mondal et al, 2012;Xu et al, 2010). That is further supported by findings showing that a high-fat diet-induced ER stress in VAT and SAT of mice reduced the release of adiponectin, and that reduction of ER stress increases extracellular adiponectin levels (Torre-Villalvazo et al, 2018). Thus, ER stress present in the adipose tissue of patients with diabesity could result in reducing the adiponectin level in the plasma of these subjects.…”

Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

“…In the present study, we found that ER stress inducers such as thapsigargin or tunicamycin largely suppressed adipsin expression in mature 3T3-L1 adipocytes, indicating that ER stress downregulates adipsin in a cell-intrinsic manner. However, previous studies have shown that expression of other adipokines, such as adiponectin and resistin, was also reduced by treatment with the ER stress inducers in both adipose tissues and cultured adipocytes [15,22,23]. In addition, expression of C/EBPα and PPARγ was suppressed by the ER stress inducers in mature 3T3-L1 adipocytes [15,16].…”