Obesity is characterized by an accumulation of macrophages in adipose, some of which form distinct crown-like structures (CLS) around fat cells. While multiple discrete adipose tissue macrophage (ATM) subsets are thought to exist, their respective effects on adipose tissue, and the transcriptional mechanisms that underlie the functional differences between ATM subsets, are not well understood. We report that obese fat tissue of mice and humans contain multiple distinct populations of ATMs with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. Mouse Ly6c ATMs reside outside of CLS and are adipogenic, while CD9 ATMs reside within CLS, are lipid-laden, and are proinflammatory. Adoptive transfer of Ly6c ATMs into lean mice activates gene programs typical of normal adipocyte physiology. By contrast, adoptive transfer of CD9 ATMs drives gene expression that is characteristic of obesity. Importantly, human adipose tissue contains similar ATM populations, including lipid-laden CD9 ATMs that increase with body mass. These results provide a higher resolution of the cellular and functional heterogeneity within ATMs and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related sequela.

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.

Adipose tissue insulin resistance due to loss of PI3K p110␣ leads to decreased energy expenditure and obesity. Am J Physiol Endocrinol Metab 306: E1205-E1216, 2014. First published April 8, 2014 doi:10.1152/ajpendo.00625.2013.-Adipose tissue is a highly insulin-responsive organ that contributes to metabolic regulation. Insulin resistance in the adipose tissue affects systemic lipid and glucose homeostasis. Phosphoinositide 3-kinase (PI3K) mediates downstream insulin signaling in adipose tissue, but its physiological role in vivo remains unclear. Using Cre recombinase driven by the aP2 promoter, we created mice that lack the class 1A PI3K catalytic subunit p110␣ or p110␤ specifically in the white and brown adipose tissue. The loss of p110␣, not p110␤, resulted in increased adiposity, glucose intolerance and liver steatosis. Mice lacking p110␣ in adipose tissue exhibited a decrease in energy expenditure but no change in food intake or activity compared with control animals. This low energy expenditure is a consequence of low cellular respiration in the brown adipocytes caused by a decrease in expression of key mitochondrial genes including uncoupling protein-1. These results illustrate a critical role of p110␣ in the regulation of energy expenditure through modulation of cellular respiration in the brown adipose tissue and suggest that compromised insulin signaling in adipose tissue might be involved in the onset of obesity. phosphoinositide 3-kinase; obesity; insulin; energy expenditure; brown adipose tissue OBESITY IS A PANDEMIC that already affects over 10% of the world's population (3). Obesity is tightly linked to the onset of type 2 diabetes and metabolic syndrome and contributes to increased mortality rates (1, 44). Despite its high prevalence, the underlying causes of obesity are not fully understood. The leptin receptor mutant db/db mouse is a well-studied model of severe obesity, diabetes, and dyslipidemia (27); however, its relevance to the human disorder is limited, since the vast majority of obese patients do not have leptin receptor mutations (21). Insulin receptor (IR) knockout mice have provided unique insight into how insulin resistance in the liver, muscle or adipose tissue affects adiposity and glucose homeostasis. Muscle-specific IR knockout (MIRKO) mice exhibited normal glucose tolerance associated with increased adiposity, whereas mice with liver-specific ablation of the IR (LIRKO) were glucose intolerant and had normal fat mass (10, 39). The fat-specific IR knockout mouse (FIRKO) exhibited reduced adiposity and normal or improved glucose tolerance (7).Adipose tissue is a highly insulin-responsive organ that contributes to the regulation of whole body glucose and lipid homeostasis. White adipose tissue (WAT) stores triglycerides, which are broken down to produce energy during times of caloric need. WAT also acts as an endocrine organ by secreting adipokines such as leptin, which acts in energy sensing and pubertal development (36). Brown adipose tissue (BAT) is responsible for the production...

Authorship note: S. Song and SD are co-first authors. Conflict of interest: BJB is an inventor on a US patent application (US20200071370A1, Cell-penetrating peptides that inhibit IRF5 nuclear localization), assigned to Rutgers. BJB and S. Sun are inventors on a US provisional patent application (62/844,894, Inhibition of IRF5 protects from lupus onset and severity), assigned to Feinstein Institutes.

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