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Alan Saltiel and his colleagues report that the approved drug amlexanox, currently used to treat asthma and canker sores, is a relatively specific inhibitor of the noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) and that it improves metabolic disease in mouse genetic and dietary models of obesity. These results suggest this drug may be repurposed to treat obesity and insulin resistance.

Previous studies suggested that glycogen metabolism played a role in beiging of subcutaneous adipocytes. This work identifies a β-adrenergic–driven transcriptional program that promotes glycogen synthesis and turnover during thermogenic activation of adipocytes. PGC1α and estrogen-related receptors (ERRs) cooperatively sustain this program by regulating chromatin accessibility and gene expression.

Neutrophil-derived IL-1β has a role in preserving lipid stores during metabolic stress.

The drug amlexanox is known to improve obesity-related metabolic dysfunction in mice. Here the authors show that this effect is mediated by interleukin-6 secreted from subcutaneous adipocytes, which then inhibits gluconeogenesis in the liver by phosphorylating the hepatic transcription factor Stat3.

The worldwide incidence of type 2 diabetes has reached epidemic proportions. More effective pharmaceutical options for the treatment of this devastating and costly disease are urgently needed. Dan Lazar and Alan Saltiel examine the exciting possibility that lipid phosphatases might provide a novel class of drug discovery targets for type 2 diabetes.

Increased glycogen metabolism in adipocytes leads to expression of uncoupling protein 1, thereby linking glucose metabolism to thermogenesis.

Adipose tissue inflammation is an adaptive response to overnutrition in the early stages of obesity, but later becomes maladaptive. Here, Reilly and Saltiel review the cellular and molecular mechanisms of obesity-induced inflammation in adipose tissue and discuss potential therapeutic approaches.

Although it is generally considered a proinflammatory cytokine, interleukin 6 (IL-6) has anti-inflammatory effects in macrophages by sensitizing them to IL-4 through upregulation of the IL-4 receptor.

Xia et al. show that the activity of the small GTPase RalA is increased in white adipocytes in diet-induced obese mice. RalA enhances mitochondrial fission and therefore reduces energy expenditure, which contributes to weight gain.

Increased infiltration of adipose tissue macrophages (ATMs) and their subsequent inflammatory effects are implicated in the development of insulin resistance among individuals with obesity. Interestingly, new data published in Cell Metabolism suggest that ATMs might also have important noninflammatory roles in lipid trafficking and its metabolic consequences.

Obesity generates a proinflammatory environment in adipose tissue, but the factors that initiate this inflammatory cascade have been unclear. Three studies now show that alterations in the composition of adipose tissue T cells occur early in obesity and shape the relationship between immunity and metabolism (pages 914–920, 921–929 and 930–939).

Here, Reilly et al. show that catecholamines control the balance between oxidation and re-esterification of fatty acids in white adipocytes through serine phosphorylation of STAT3, which inhibits the re-esterification enzyme GPAT3 via a non-genomic mechanism.

The glucose transporter GLUT4 ensures controlled glucose uptake into fat and muscle cells. By targeting several steps in the membrane trafficking of GLUT4, insulin signalling allows tight regulation of glucose homeostasis and prevents the development of insulin resistance.

How do exocytic vesicles disengage from the exocyst complex? Phosphorylation of the RalA GTPase effector Sec5, rather than RalA inactivation per se, is now shown to mediate dissociation of the Sec5–RalA complex.

Immune cells called regulatory T cells accumulate in fat during ageing. The anti-inflammatory activity of these cells worsens age-associated defects in metabolism, in contrast to its effect in obesity. See Letter p.137

p62 is a signaling hub protein that contributes to the control of energy expenditure. Here the authors investigate the relative roles of p62 and a similar protein, NBR1, and show that NBR1 is required for the repression of thermogenesis in adipocytes occurring in the absence of p62.

Restriction of FXR agonism to the gut improves obesity and diabetes.

Glucose transport into the cell is a delicate process that is highly responsive to insulin. A newly identified protein that may tether to the glucose transporter helps keep glucose traffic running smoothly in human cells.

Obesity and insulin resistance enjoy a complex relationship that gives rise to a range of metabolic disorders, including type 2 diabetes, dyslipidemia and coagulation disorders. Teasing apart this relationship could yield new therapies to treat some of these conditions and two new reports point to the adipocyte-secreted protein, adiponectin, as a new molecular target. (pages 941–946 and pages 947–953)

The phosphatase SHIP2 has been the focus of drug development efforts for diabetes. This distinction is based in part on work suggesting that the molecule is central to the regulation of glucose levels in tissues and blood. An analysis of a SHIP2 knockout mouse changes this viewpoint and provides new directions for therapeutic intervention (pages 199–205).

Obesity is a manifestation of a positive energy balance in which energy intake exceeds energy expenditure, thus often leading to insulin resistance and type 2 diabetes. A new study provides evidence that pharmacological inhibition of hyaluronan, an extracellular-matrix glycosaminoglycan, increases energy expenditure and insulin sensitivity by activating thermogenesis in brown adipose tissue.