Abstract
Obesity is a state of low-grade chronic inflammation that causes multiple metabolic diseases. During obesity, signalling via cytokines of the TNF family mediate cell death and inflammation within the adipose tissue, eventually resulting in lipid spill-over, glucotoxicity and insulin resistance. These events ultimately lead to ectopic lipid deposition, glucose intolerance and other metabolic complications with life-threatening consequences. Here we review the literature on how inflammatory responses affect metabolic processes such as energy homeostasis and insulin signalling. This review mainly focuses on the role of cell death in the adipose tissue as a key player in metabolic inflammation.
Facts
- Obesity induces cell death and inflammation in the adipose tissue.
- Cell death within the adipose tissue induces inflammation-associated metabolic syndromes.
- Cell death machinery and NF-κB-mediated inflammation regulate energy homeostasis and insulin sensitivity.
- The crosstalk between adipocytes and adipose-tissue macrophages initiates systemic metabolic inflammation during obesity.
Open questions
- Is cell death required to induce metabolic inflammation?
- Is there a “healthy” and an “unhealthy” way to die during excessive lipid uptake? And does it depend on the metabolic organ in which these events happen?
- Does activation of cell death machinery directly modulate metabolic processes, such as energy expenditure, during obesity?
Introduction
Obesity is now considered a global disease as it affects over 1.9 billion people worldwide [1]. Obesity is a state of low-grade chronic inflammation that causes an array of different metabolic disorders, including insulin resistance (IR), Type 2 Diabetes, hypertension, cardiovascular disease, dyslipidemia and even cancer [2]. In recent years, studies have demonstrated a strong link between overnutrition and activation of the innate immune system as the leading cause of energy imbalance in most organs [1].
The white adipose tissue (WAT) is an endocrine and lipid storage organ that plays a pivotal role in obesity-associated disorders. Efficient lipid storage prevents ectopic lipid deposition and toxic lipid accumulation (lipotoxicity) in non-specialised organs, such as muscle, liver and heart, and it correlates with preserved metabolic function [3]. The WAT is mainly composed of preadipocytes or adipocyte precursors (AP) and adipocytes as well as of different types of immune cells, including macrophages, dendritic cells, T cells and B cells. Immune cells in WAT collectively monitor and maintain adipocyte integrity, metabolic function and hormonal sensitivity [4, 5]. Macrophages are the most abundant innate immune cells infiltrating and accumulating into WAT; they constitute up to 40–50% of all WAT cells. During obesity, adipose tissue macrophages (ATM) are polarized into pro-inflammatory M1-like macrophages and secrete many pro-inflammatory cytokines, such as TNF, capable of impairing insulin signalling, therefore, promoting the progression of IR. Although many factors are involved in the increased recruitment of macrophages into WAT during obesity, it is mainly attributed to adipocyte death. Macrophages are generally found surrounding dead adipocytes forming the typical crown-like structure (CLS), and the presence of these structures is directly associated with IR in mice and men [6, 7].
Adipocytes do not only play a role in lipid storage, but also on metabolism and inflammation through the secretion of cytokines and adipokines, such as leptin and adiponectin [8]. Leptin is considered to be the satiety hormone and it has pro-inflammatory functions [9, 10]. Adiponectin, in contrast, has anti-inflammatory properties by downregulating cytokines, such as TNF, MCP-1, and IL-6 [11, 12]. In obese individuals leptin plasma levels raises while adiponectin tends to decrease [13, 14]. Adipokines regulate energy expenditure as well as glucose and lipid metabolism through the metabolic regulator, AMP-activated protein kinase (AMPK) [15]. AMPK is an intercellular energy sensor, which is sensitive to AMP:ATP ratios [16]. AMPK promotes energy conservation by shutting down anabolism (gluconeogenesis, fatty acid synthesis) and activating catabolic pathways (β-oxidation, ATP production) [17] (Fig. 1). Even though this kinase responds to several stimuli that exhaust ATP levels in cells, it can also be phosphorylated, and activated, in response to adiponectin and leptin stimulation in organs such as skeletal muscle [18, 19]. The only exception to this, is the hypothalamus, where leptin acts by decreasing AMPK activity, potentially explaining why leptin specialises in suppressing food intake [19].
In obesity, there is a dynamic remodelling of the WAT in which adipocytes can either increase in size (hypertrophy) or in number, following differentiation from AP, or adipogenesis, (hyperplasia). WAT can be classified in two main compartments, subcutaneous (SAT) and visceral (VAT). Each of them bearing specific metabolic functions and characteristics. They present different patterns of gene expression, including genes involved in adipocyte function and development [20]. Notably, VAT-APs are more resistant to differentiation into adipocytes and are more sensitive to cell death than SAT-APs [21]. This phenomena can also greatly contribute to inflammation and metabolic syndromes [8]. In general terms, whereas SAT expands by adipocyte hyperplasia, VAT predominantly expands by adipocyte hypertrophy in response to excess food intake [22]. Indeed, VAT is the fat depot that undergoes major cell death and inflammatory procceses [23]. Hypertrophic adipocytes secrete inflammatory cytokines such as TNF and IL-6, causes recruitment and activation of immune cells whilst reducing adiponectin and anti-inflammatory cytokines production [24, 25]. This state of low-grade chronic inflammation eventually results in lipotoxicity, systemic inflammation and metabolic syndromes. Furthermore, activated macrophages during obesity, although at first essential for healthy tissue expansion and remodelling, when sustained they can lead to fibrosis and impaired adipogenesis [21]. These events result in a vicious cycle of inflammation, cell death and metabolic dysbalance that together cause metabolic syndromes. Notably, this condition also promotes a protumorigenic microenvironment that induces or supports tumour growth in cancers that are linked to obesity such as breast, liver and colon carcinomas [26].
Inflammation, cell death and metabolic processes are highly interlinked processes during obesity and a tight balance between these processes is crucial to prevent metabolic diseases. Here we review the literature of the signalling events governed by the pleiotropic immune mediator, TNF, and a pathogen sensing system, the inflammasome, during obesity with a focus on the current knowledge regarding cell death regulation in the WAT and its impact on metabolic inflammation.
The horror at their crimes is lost in the admiration at their skills: culprits TNF and IL-1β
The key importance of TNF signalling in obesity-induced inflammation and metabolic complications was vastly demonstrated in animal models and also in humans. Indeed, although still a matter of debate, TNF neutralisation improves glucose homeostasis and reduces diabetes risk in human patients [27]. Likewise, IL-1β is an important regulator of inflammation during obesity as its neutralisation ameliorates obesity-induced inflammation [28].
The signalling cascade that is unleashed following binding of TNF to its cognate receptor, TNFR1, results in activation of the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) via the formation of a receptor signalling complex, also known as complex I [29] (Figs. 1 and 2). This complex facilitates the activation of IKKɑ/β/ɣ(NEMO) and TAK1/TAB1/2 complexes. This leads to the transcriptional activation of genes, amongst which chemokines and cytokines including TNF itself, IL-6, and other prosurvival proteins, such as BCL2 and cFLIP. In principle, the latter prevents induction of cell death via intrinsic or extrinsic pathways, respectively [30]….
