Adipose tissue macrophage (ATM)-driven inflammation plays a key role in insulin resistance; however, factors activating ATMs are poorly understood. Using a proteomics approach, we show that markers of classical activation are absent on ATMs from obese humans, but readily detectable on airway macrophages of patients with cystic fibrosis, a disease of chronic bacterial infection. Moreover, treating macrophages with glucose, insulin, and palmitate – conditions characteristic of the metabolic syndrome – produces a ‘metabolically-activated’ phenotype distinct from classical activation. Markers of metabolic activation are expressed by pro-inflammatory ATMs in obese humans/mice and are positively correlated with adiposity. Metabolic activation is driven by independent pro- and anti-inflammatory pathways, which regulate balance between cytokine production and lipid metabolism. We identify PPARγ and p62/SQSTM1 as two key proteins that promote lipid metabolism and limit inflammation in metabolically-activated macrophages. Collectively, our data provide important mechanistic insights into pathways that drive the metabolic disease-specific phenotype of macrophages.

The objective of this comprehensive review is to summarize and discuss the available evidence of how adipose tissue inflammation affects insulin sensitivity and glucose tolerance. Low-grade, chronic adipose tissue inflammation is characterized by infiltration of macrophages and other immune cell populations into adipose tissue, and a shift towards more pro-inflammatory subtypes of leukocytes. The infiltration of pro-inflammatory cells in adipose tissue is associated with an increased production of key chemokines such as C-C motif chemokine ligand 2, pro-inflammatory cytokines including tumor necrosis factor α and interleukins 1β and 6, as well as reduced expression of the key insulin sensitizing adipokine, adiponectin. In both rodent models and humans, adipose tissue inflammation is consistently associated with excess fat mass and insulin resistance. In humans, associations with insulin resistance are stronger and more consistent for inflammation in visceral as opposed to subcutaneous fat. Further, genetic alterations in mouse models of obesity that reduce adipose tissue inflammation are – almost without exception - associated with improved insulin sensitivity. However, a dissociation between adipose tissue inflammation and insulin resistance can be observed in very few rodent models of obesity as well as in humans following bariatric surgery- or low-calorie diet-induced weight loss, illustrating that the etiology of insulin resistance is multifactorial. Taken together, adipose tissue inflammation is a key factor in the development of insulin resistance and type 2 diabetes in obesity, along with other factors that likely include inflammation and fat accumulation in other metabolically active tissues.

Sprint interval training (SIT) and traditional endurance training elicit similar physiological adaptations. From the perspective of metabolic function, superior glucose regulation is a common characteristic of endurance-trained adults. Accordingly, we have investigated the hypothesis that short-term SIT will increase insulin sensitivity in sedentary/recreationally active humans. Thirty one healthy adults were randomly assigned to one of three conditions: (1) −1 min −1 : % EE 11 ± 2, 14 ± 3, 23 ± 2 vs. 11 ± 1, 16 ± 2, 25 ± 3; P = 0.79). Combined data from both studies revealed no effect of SIT on fasted circulating concentrations of glucose, insulin, adiponectin, pigment epithelial-derived factor, non-esterified fatty acids or noradrenaline (all P > 0.05). Sixteen minutes of high-intensity exercise over 14 days augments insulin sensitivity but does not affect the thermogenic response to β-AR stimulation. Abbreviations β-AR, beta-adrenergic receptor; EE, energy expenditure; FFM, fat-free mass; GLUT4, glucose transporter 4; NEFA, non-esterified fatty acids; PEDF, pigment epithelial-derived factor; RER, respiratory exchange ratio; SIT, sprint interval training;V O 2 ,peak , peak oxygen uptake.

Aims/hypothesis Mounting evidence indicates that Roux-en-Y gastric bypass (RYGB) ameliorates type 2 diabetes, but randomised trials comparing surgical vs nonsurgical care are needed. With a parallel-group randomised controlled trial (RCT), we compared RYGB vs an intensive lifestyle and medical intervention (ILMI) for type 2 diabetes, including among patients with a BMI <35 kg/m2. Methods By use of a shared decision-making recruitment strategy targeting the entire at-risk population within an integrated community healthcare system, we screened 1,808 adults meeting inclusion criteria (age 25–64, with type 2 diabetes and a BMI 30–45 kg/m2). Of these, 43 were allocated via concealed, computer-generated random assignment in a 1:1 ratio to RYGB or ILMI. The latter involved ≥45 min of aerobic exercise 5 days per week, a dietitian-directed weight- and glucose-lowering diet, and optimal diabetes medical treatment for 1 year. Although treatment allocation could not be blinded, outcomes were determined by a blinded adjudicator. The primary outcome was diabetes remission at 1 year (HbA1c <6.0% [<42.1 mmol/mol], off all diabetes medicines). Results Twenty-three volunteers were assigned to RYGB and 20 to ILMI. Of these, 11 withdrew before receiving any intervention. Hence 15 in the RYGB group and 17 in the IMLI group were analysed throughout 1 year. The groups were equivalent regarding all baseline characteristics, except that the RYGB cohort had a longer diabetes duration (11.4±4.8 vs 6.8±5.2 years, p=0.009). Weight loss at 1 year was 25.8±14.5% vs 6.4±5.8% after RYGB vs ILMI, respectively (p<0.001). The ILMI exercise programme yielded a 22±11% increase in V̇O2max (p <0.0001), whereas V̇O2max after RYGB was unchanged. Diabetes remission at 1 year was 60.0% with RYGB vs 5.9% with ILMI (p=0.002). The HbA1c decline over 1 year was only modestly more after RYGB than ILMI: from 7.7±1.0% (60.7 mmol/mol) to 6.4 ±1.6% (46.4 mmol/mol) vs 7.3±0.9% (56.3 mmol/mol) to 6.9±1.3% (51.9 mmol/mol), respectively (p=0.04); however, this drop occurred with significantly fewer or no diabetes medications after RYGB. No life-threatening complications occurred. Conclusions/interpretation Compared with the most rigorous ILMI yet tested against surgery in a randomised trial, RYGB yielded greater type 2 diabetes remission in mild-to-moderately obese patients recruited from a well-informed, population-based sample. Trial registration ClinicalTrials.gov NCT01295229

Mountain rivers can be subject to strong constraints imposed by changes in gradient and grain size supplied by processes such as glaciation and rockfall. Nonetheless, adjustments in the channel geometry and hydraulics of mountain rivers at the reach scale can produce discernible patterns analogous to those in fully alluvial rivers. Mountain rivers can differ in that imposed reach-scale gradient is an especially important control on reach-scale channel characteristics, as indicated by examination of North St Vrain Creek in Colorado.North St Vrain Creek drains 250 km 2 of the Rocky Mountains. We used 25 study reaches within the basin to examine controls on reach-scale channel geometry. Variables measured included channel geometry, large woody debris, grain size, and mean velocity. Drainage area at the study reaches ranged from 2·2 to 245 km 2 , and gradient from 0·013 to 0·147 m m −1 . We examined correlations among (1) potential reach-scale response variables describing channel bankfull dimension and shape, hydraulics, bedform wavelength and amplitude, grain size, flow resistance, standard deviation of hydraulic radius, and volume of large woody debris, and (2) potential control variables that change progressively downstream (drainage area, discharge) or that are likely to reflect a reach-specific control (bed gradient). We tested the hypothesis that response variables correlate most strongly with local bed gradient because of the segmented nature of mountain channels.Results from simple linear regression analyses indicate that most response variables correlate best with gradient, although channel width and width/depth ratio correlate best with discharge. Multiple regression analyses using Mallow's C p selection criterion and log-transformation of all variables produced similar results in that most response variables correlate strongly with gradient. These results suggest that the hypothesis is partially supported: channel bed gradient is likely to be a good predictor for many reach-scale response variables along mountain rivers, but discharge is also an important predictor for some response variables.

Objective Type 2 diabetes (T2D) commonly goes into remission following Roux-en-Y gastric bypass (RYGB). As the mechanisms remain incompletely understood, we hypothesized that a reduction in adipose tissue inflammation may contribute to these metabolic improvements. Therefore, we investigated whether RYGB reduces adipose tissue inflammation compared to equivalent weight loss from an intensive lifestyle intervention. Methods Sixteen people with obesity and T2D were randomized to RYGB or lifestyle intervention. Fasting blood and subcutaneous abdominal adipose tissue were obtained before and after the loss of ~7% of baseline weight. Adipose tissue inflammation was assessed by whole-tissue gene expression and flow cytometry-based quantification of tissue leukocytes. Results At 7% weight loss, insulin and metformin use were reduced among the RYGB but not the Lifestyle cohort, while fasting glucose and insulin declined in both. Adipose tissue inflammation increased modestly after RYGB, and to a similar extent following non-surgical weight loss. In both groups, the number of neutrophils increased several-fold (P<0.001), mRNA levels of the pro-inflammatory cytokine interleukin-1β increased (P=0.037), and mRNA expression of the anti-inflammatory and insulin-sensitizing adipokine, adiponectin, decreased (P=0.010). Conclusions A reduction in adipose tissue inflammation is not one of the acute weight loss-independent mechanisms through which RYGB exerts its anti-diabetes effects.

In healthy adults, total 8-d ad libitum energy intake was increased in individuals consuming SSBs compared with aspartame-sweetened beverages. The energy overconsumption observed in individuals consuming SSBs occurred independently of the relative amounts of fructose and glucose in the beverages. These trials were registered at clinicaltrials.gov as NCT00475475 and NCT01424306.

Excessive amounts of fructose, HFCS, and glucose from SSBs consumed over 8 d did not differentially affect low-grade chronic systemic inflammation in normal-weight to obese adults. This trial was registered at clinicaltrials.gov as NCT01424306.