Inflammatory links between obesity and metabolic disease (original) (raw)

The discovery of ATM activation with obesity sparked a wave of interest into how immune responses intersect with obesity (31, 32). We know now that the dynamic regulation of inflammatory cells with obesity is not limited to fat and that inflammatory and metabolic signals converge in a myriad of contexts. This provides new opportunities to understand the pathogenesis of many organ-specific diseases associated with obesity (Figure 1).

Pancreatic islets. Relevant to type 2 diabetes is the demonstration that inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes (33, 34). The mediators of these effects are multifactorial and likely involve cytokines produced by β cells themselves (35). As in adipose tissue, macrophages accumulate in islets with DIO and may be a significant source of proinflammatory cytokines that block β cell function (36). This point is often ignored in studies that manipulate macrophages by Cre-mediated recombination or BM transplantation and may be an underappreciated mechanism for protection from diabetes in many animal models.

Adipose tissue. Adipose tissue insulin resistance and dysfunctional lipid storage in adipocytes are sentinel events in the progression toward metabolic dysregulation with obesity. Forced expansion of adipose tissue by transgenic overexpression of the adipokine adiponectin prevents metabolic disease despite massive obesity (37). Impaired lipogenic/adipogenic capacity is associated with increased visceral fat in obese adolescents (38), and smaller omental adipocytes is a feature of metabolically healthy obese adults (39). These findings support the model that lipid “spillover” from fat promotes metabolic disease by fostering ectopic lipid deposition. Since an estimated excess of 20–30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass (40).

Inputs into this inflammatory response include ER stress, adipose tissue hypoxia, and adipocyte death (41–43). Since changes in ATM number and gene expression profile occur coincident with the development of insulin resistance (41, 44), it is possible that ATMs are merely effectors of a coordinated inflammatory response that includes the accumulation of CD8+ T cells, Th1-polarized CD4+ T cells, and the loss of Tregs (29, 44). NK cells, NKT cells, and mast cells are also implicated in metainflammation (40, 45, 46). Overall, our challenge in understanding adipose tissue inflammation will be to identify the temporal and spatial interactions between leukocytes in fat in the context of inflammatory initiation as well as their resolution.

Inflammation in liver and muscle. Nonalcoholic fatty liver disease (NAFLD) is a strong risk factor for insulin resistance, nonalcoholic steatohepatitis, and dyslipidemia, independent of visceral adiposity (47). Many of the signaling pathways involved in both inflammation and metabolism are elevated in steatotic liver (e.g., JNK, TLR4, ER stress). Similar to the effects of obesity on adipose tissue, NAFLD is associated with an increase in M1/Th1 cytokines and quantitative increases in immune cells (48–50). In addition, modulation of PPARδ-dependent M2 polarization pathways protects mice from NAFLD (17, 26). These effects may be mediated via Kupffer cells resident in the liver, or by unique cell populations recruited to the liver with obesity (51).

There is also evidence of increased inflammatory cytokine production and increased inflammation in skeletal muscle in obesity (52). Myocytes have the capacity to respond to inflammatory signals via pattern recognition receptors (PRRs) such as TLR4 with direct metabolic effects (53). Muscle inflammation may be linked to infiltrating macrophages that are induced in obese muscle and have properties of M1 activation (23, 54). This topic is complicated by the fact that leukocyte trafficking of monocytes and macrophages is intrinsically linked to muscle injury and repair (55), increasing the challenge of de-convoluting the acute and chronic inflammatory changes in muscle with DIO.

Hypothalamic inflammation and obesity. Human genome wide association studies have identified loci near or within numerous neuronal genes that affect BMI, suggesting that variation in the central control of metabolism plays a prominent role in genetic obesity risk (56). Lipid infusion and a high-fat diet (HFD) activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage (57). With DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS (58, 59). Part of this effect is mediated by saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling (60). Disruption of signaling through TLR4/MyD88, IKKβ/NF-κB, and ER stress pathways in neurons protects mice from DIO and its downstream metabolic effects (60–62).

The effects of brain inflammation on the metabolic function of peripheral tissues are broad. Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension (63–65). Many of these effects are generated by signals from the sympathetic nervous system, which is also capable of inducing inflammatory changes in adipose tissue in response to neuronal injury (66). A future challenge is to understand how inflammatory signals in the brain generate responses that in some cases generate negative energy balance (anorexia), while in other cases generates positive energy balance (weight gain) (67).

The dynamic interplay between hypothalamic inflammation and obesity suggest additional targets for antiinflammatory therapies in obesity. A key extension of these observations is the potential that antiinflammatory pathways may counteract these CNS inflammatory events and improve leptin sensitivity. Recent evidence suggests that IL-6 and IL-10 are involved in the exercise-induced suppression of hyperphagia and suppress IKKβ/NF-κB and ER stress in the brain (68). The IKKβ/NF-κB inhibitor sodium salicylate is also capable of preventing the accumulation of ceramides in the hypothalamus with lipid infusion (58).

Development. Another intriguing possible link between inflammation and the risk for obesity involves events in early embryonic development. Epidemiologic and animal models have demonstrated a strong association between the prenatal and perinatal environment and obesity-associated diseases (69). The risk for obesity and metabolic disorders follows a U-shaped distribution based on birth weight, with increased risk in low- and high-birth-weight infants (70, 71). Since pregnancy represents a physiologic inflammatory state involving the innate and acquired immune system, inflammatory mechanisms may contribute to the in utero programming of nutrient metabolism (72). Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73). Placental inflammation is a characteristic of maternal obesity, a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74). Inflammatory disturbances in the placenta may alter the nutrient set points established early in life and predispose to an accelerated pattern of catch-up growth that contributes to the risk for later obesity, especially in low-birth-weight infants (75, 76). The concept that inflammatory networks can influence the predilection toward obesity is supported by the findings that variation in obesity susceptibility between mouse strains is intrinsically linked to the inflammatory networks and leukocyte composition of adipose tissue established prior to HFD exposure (77). Overall, there is much to be learned about how maternal and paternal factors contribute to the epigenetic programming of metabolism genes that contribute to long-term effects on adult body weight (78, 79). It will be interesting to see whether inflammatory response genes are coordinately altered with metabolic gene networks based on the in utero environment.