Metabolic Inflammation-Differential Modulation by Dietary Constituents

Abstract

Obesity arises from a sustained positive energy balance which triggers a pro-inflammatory response, a key contributor to metabolic diseases such as T2D. Recent studies, focused on the emerging area of metabolic-inflammation, highlight that specific metabolites can modulate the functional nature and inflammatory phenotype of immune cells. In obesity, expanding adipose tissue attracts immune cells, creating an inflammatory environment within this fatty acid storage organ. Resident immune cells undergo both a pro-inflammatory and metabolic switch in their function. Inflammatory mediators, such as TNF-α and IL-1β, are induced by saturated fatty acids and disrupt insulin signaling. Conversely, monounsaturated and polyunsaturated fatty acids do not interrupt metabolism and inflammation to the same extent. AMPK links inflammation, metabolism and T2D, with roles to play in all and is influenced negatively by obesity. Lipid spillover results in hepatic lipotoxicity and steatosis. Also in skeletal muscle, excessive FFA can impede insulin's action and promote inflammation. Ectopic fat can also affect pancreatic β-cell function, thereby contributing to insulin resistance. Therapeutics, lifestyle changes, supplements and dietary manipulation are all possible avenues to combat metabolic inflammation and the subsequent insulin resistant state which will be explored in the current review.

Keywords: adipose tissue; diet; fatty acids; insulin resistance; liver; metabolic-inflammation; muscle; nutrition; pancreas.

Figure 1

Metabolic-inflammation: Implication of free fatty acid (FFA) driven insulin resistance on the major metabolic organs. As adipose tissue expands due to excess nutrients, immune cells infiltrate causing chronic low-grade inflammation and metabolic changes. Ectopic lipid spill-over from the adipose to the liver, muscle and pancreas results in glucotoxicity and lipotoxicity. All of these disruptions culminate in impaired insulin signaling, dysregulated glucose homeostasis and development of insulin resistance and type 2 diabetes (T2D). Differential modulation by fatty acids occurs, whereby saturated fatty acids (SFA) exacerbate the situation, while monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) reduce this metabolic inflammatory state. (This figure was prepared using the Servier medical art website [4].

Figure 2

Inflammatory pathways in M1 and M2 macrophages. M1 pro-inflammatory macrophages are induced by saturated fatty acids (SFA) and lipopolysaccharide (LPS) to generate pro-inflammatory signaling through nuclear factor kappa B (NFkB) to produce tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Subsequent stimulation by ceramides, adenosine triphosphate (ATP) or reactive oxygen species (ROS) leads to assembly of the nod-like receptor (Nlrp3) inflammasome and processing of pro-interleukin-1 beta (IL1β) to active IL-1β through cleavage by caspase-1. Pro-inflammatory cytokines negatively impact glucose homeostasis and insulin signaling, resulting in insulin resistance in neighbouring cells. M2 anti-inflammatory macrophages are induced by monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) acting via receptors, which are currently unidentified, with increased interleukin-10 (IL-10) secretion along with a reduction in pro-inflammatory markers. This results in improved insulin sensitivity and a less inflammatory environment. TLR = toll-like receptor, ASC = apoptosis like speck protein, GLUT4 = glucose transporter type 4, IRS = insulin receptor substrate, FAS = fatty acid synthase. PPARγ = peroxisome proliferator activated receptor gamma, OA = oleic acid, PO = palmitoleate, EPA = eicosapentaenoic acid, DHA = docosahexaenoic, ERK = extracellular regulated kinase. (This figure was prepared using the Servier medical art website [4]).

Figure 3

Integration of metabolism and immune responses. Obesity and SFA drive an M1 pro-inflammatory phenotype in macrophages which favours glycolysis for ATP generation and leads to TCA cycle fragmentation with a break at the succinate dehydrogenase step. This break in the TCA cycle results in increased succinate and citrate accumulation. Citrate accumulation impedes insulin sensitivity by increasing lipogenesis and mitochondrial stress. Succinate inhibits PHD, stabilizing HIF-1α leading to activation of the pro-inflammatory cytokine IL-1β. While MUFA and PUFA drive an anti-inflammatory M2 phenotype which favours the more energy efficient process of oxidative phosphorylation, with increased fatty acid oxidation and glutamine metabolism. (This figure was prepared using the Servier medical art website [4]).