Ketone bodies are elevated in response to fasting, a low-carbohydrate ketogenic diet or high-intensity exercise. Vishwa Deep Dixit and colleagues report that one metabolite, β-hydroxybutyrate, inhibits the NLRP3 inflammasome. In vivo, β-hydroxybutyrate is anti-inflammatory and suppresses NLRP3-mediated inflammatory disease. The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP1. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet2. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown2,3,4,5,6. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein–coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome–mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle–Wells syndrome, familial cold autoinflammatory syndrome and urate crystal–induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.

Objective: This review will focus on the immunological aspects of adipose tissue and its potential role in development of chronic inflammation that instigates obesity‐associated comorbidities.Methods: The review used PubMed searches of current literature to examine adipose tissue leukocytosis.Results and Conclusions: The adipose tissue of obese subjects becomes inflamed and contributes to the development of insulin resistance, type 2 diabetes, and metabolic syndrome. Numerous immune cells including B cells, T cells, macrophages, and neutrophils have been identified in adipose tissue, and obesity influences both the quantity and the nature of immune cell subtypes, which emerges as an active immunological organ capable of modifying whole‐body metabolism through paracrine and endocrine mechanisms. Adipose tissue is a large immunologically active organ during obesity and displays hallmarks of both and innate and adaptive immune response. Despite the presence of hematopoietic lineage cells in adipose tissue, it is unclear whether the adipose compartment has a direct role in immune surveillance or host defense. Understanding the interactions between leukocytes and adipocytes may reveal the clinically relevant pathways that control adipose tissue inflammation and is likely to reveal mechanisms by which obesity contributes to increased susceptibility to both metabolic and certain infectious diseases.

Context: Compared with glucose-sweetened beverages, consumption of fructose-sweetened beverages with meals elevates postprandial plasma triglycerides and lowers 24-h insulin and leptin profiles in normal-weight women. The effects of fructose, compared with glucose, ingestion on metabolic profiles in obese subjects has not been studied. Objective: The objective of the study was to compare the effects of fructose- and glucose-sweetened beverages consumed with meals on hormones and metabolic substrates in obese subjects. Design and Setting: The study had a within-subject design conducted in the clinical and translational research center. Participants: Participants included 17 obese men (n = 9) and women (n = 8), with a body mass index greater than 30 kg/m². Interventions: Subjects were studied under two conditions involving ingestion of mixed nutrient meals with either glucose-sweetened beverages or fructose-sweetened beverages. The beverages provided 30% of total kilocalories. Blood samples were collected over 24 h. Main Outcome Measures: Area under the curve (24 h AUC) for glucose, lactate, insulin, leptin, ghrelin, uric acid, triglycerides (TGs), and free fatty acids was measured. Results: Compared with glucose-sweetened beverages, fructose consumption was associated with lower AUCs for insulin (1052.6 ± 135.1 vs. 549.2 ± 79.7 μU/ml per 23 h, P < 0.001) and leptin (151.9 ± 22.7 vs. 107.0 ± 15.0 ng/ml per 24 h, P < 0.03) and increased AUC for TG (242.3 ± 96.8 vs. 704.3 ± 124.4 mg/dl per 24 h, P < 0.0001). Insulin-resistant subjects exhibited larger 24-h TG profiles (P < 0.03). Conclusions: In obese subjects, consumption of fructose-sweetened beverages with meals was associated with less insulin secretion, blunted diurnal leptin profiles, and increased postprandial TG concentrations compared with glucose consumption. Increases of TGs were augmented in obese subjects with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese subjects.

Over the recent past, the importance of aberrant immune cell activation as one of the contributing mechanisms to the development of insulin-resistance and type 2 diabetes (T2D) has been recognized. Among the panoply of pro-inflammatory cytokines that are linked to chronic metabolic diseases, new data suggests that interleukin-1β (IL-1β) may play an important role in initiating and sustaining inflammation-induced organ dysfunction in T2D. Therefore, factors that control secretion of bioactive IL-1β have therapeutic implications. In this regard, the identification of multiprotein scaffolding complexes, “inflammasomes,” has been a great advance in our understanding of this process. The secretion of bioactive IL-1β is predominantly controlled by activation of caspase-1 through assembly of a multiprotein scaffold, “inflammasome” that is composed of NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) ASC (apoptosis associated speck-like protein containing a CARD) and procaspase-1. The NLRP3 inflammasome appears to be an important sensor of metabolic dysregulation and controls obesity-associated insulin resistance and pancreatic beta cell dysfunction. Initial clinical “proof of concept” studies suggest that blocking IL-1β may favorably modulate factors related to development and treatment of T2D. However, this potential therapeutic approach remains to be fully substantiated through phase-II clinical studies. Here, we outline the new immunological mechanisms that link metabolic dysfunction to the emergence of chronic inflammation and discuss the opportunities and challenges of future therapeutic approaches to dampen NLRP3 inflammasome activation or IL-1β signaling for controlling type 2 diabetes.