The association between obesity and impaired insulin sensitivity has long been recognized, although a subgroup of obese individuals seems to be protected from insulin resistance. In this study, we systematically studied differences in adipose tissue biology between insulin-sensitive (IS) and insulinresistant (IR) individuals with morbid obesity. On the basis of glucose infusion rate during euglycemic hyperinsulinemic clamps, 60 individuals with a BMI of 45 Ϯ 1.3 kg/m 2 were divided into an IS and IR group matched for age, sex, and body fat prior to elective surgery. We measured fat distribution, circulating adipokines, and parameters of inflammation, glucose, and lipid metabolism and characterized adipose tissue morphology, function, and mRNA expression in abdominal subcutaneous (sc) and omental fat. IS compared with IR obese individuals have significantly lower visceral fat area (138 Ϯ 27 vs. 316 Ϯ 91 cm 2 ), number of macrophages in omental adipose tissue (4.9 Ϯ 0.8 vs. 13.2 Ϯ 1.4%), mean omental adipocyte size (528 Ϯ 76 vs. 715 Ϯ 81 pl), circulating C-reactive protein, progranulin, chemerin, and retinol-binding protein-4 (all P values Ͻ0.05), and higher serum adiponectin (6.9 Ϯ 3.4 vs. 3.4 Ϯ 1.7 ng/ml) and omental adipocyte insulin sensitivity (all P values Ͻ0.01). The strongest predictors of insulin sensitivity by far were macrophage infiltration together with circulating adiponectin (r 2 ϭ 0.98, P Ͻ 0.0001). In conclusion, independently of total body fat mass, increased visceral fat accumulation and adipose tissue dysfunction are associated with IR obesity. This suggests that mechanisms beyond a positive caloric balance such as inflammation and adipokine release determine the pathological metabolic consequences in patients with obesity.visceral adipose tissue; insulin resistance; inflammation; adipokines; macrophages OBESITY IS ASSOCIATED WITH AN INCREASED RISK of premature death (2) and represents a fast-growing health problem that is reaching epidemic proportions worldwide (21). Obesity significantly increases the risk of developing type 2 diabetes mellitus, hypertension, coronary heart disease, stroke, and several types of cancer (42). For instance, the risk to develop type 2 diabetes is ninefold higher for obese than for lean men (45). Although there is a strong relationship between obesity and insulin resistance (1, 10, 42), and obese individuals become more insulin sensitive with weight loss (32), not all obese patients are insulin resistant (6,14).Data from the European Group for the Study of Insulin Resistance suggest that ϳ25% of obese individuals [body mass index (BMI) Ͼ35 kg/m 2 ] are insulin sensitive (14).It is clinically important to identify insulin-resistant obese persons with an increased risk for developing obesity-associated metabolic and cardiovascular diseases who, therefore, may benefit the most from losing weight (32). Insulin-resistant (IR) and insulin-sensitive (IS) obesity are not clearly defined subgroups but represent the extremes of a continuum, the characterization of which may...

Creativity is a cornerstone of what makes us human, yet the neural mechanisms underlying creative thinking are poorly understood. A recent surge of interest into the neural underpinnings of creative behavior has produced a banquet of data that is tantalizing but, considered as a whole, deeply self-contradictory. We review the emerging literature and take stock of several long-standing theories and widely held beliefs about creativity. A total of 72 experiments, reported in 63 articles, make up the core of the review. They broadly fall into 3 categories: divergent thinking, artistic creativity, and insight. Electroencephalographic studies of divergent thinking yield highly variegated results. Neuroimaging studies of this paradigm also indicate no reliable changes above and beyond diffuse prefrontal activation. These findings call into question the usefulness of the divergent thinking construct in the search for the neural basis of creativity. A similarly inconclusive picture emerges for studies of artistic performance, except that this paradigm also often yields activation of motor and temporoparietal regions. Neuroelectric and imaging studies of insight are more consistent, reflecting changes in anterior cingulate cortex and prefrontal areas. Taken together, creative thinking does not appear to critically depend on any single mental process or brain region, and it is not especially associated with right brains, defocused attention, low arousal, or alpha synchronization, as sometimes hypothesized. To make creativity tractable in the brain, it must be further subdivided into different types that can be meaningfully associated with specific neurocognitive processes.

This article outlines a framework of creativity based on functional neuroanatomy. Recent advances in the field of cognitive neuroscience have identified distinct brain circuits that are involved in specific higher brain functions. To date, these findings have not been applied to research on creativity. It is proposed that there are four basic types of creative insights, each mediated by a distinctive neural circuit. By definition, creative insights occur in consciousness. Given the view that the working memory buffer of the prefrontal cortex holds the content of consciousness, each of the four distinctive neural loops terminates there. When creativity is the result of deliberate control, as opposed to spontaneous generation, the prefrontal cortex also instigates the creative process. Both processing modes, deliberate and spontaneous, can guide neural computation in structures that contribute emotional content and in structures that provide cognitive analysis, yielding the four basic types of creativity. Supportive evidence from psychological, cognitive, and neuroscientific studies is presented and integrated in this article. The new theoretical framework systematizes the interaction between knowledge and creative thinking, and how the nature of this relationship changes as a function of domain and age. Implications for the arts and sciences are briefly discussed.

Brown fat activates uncoupled respiration to defend against cold and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that Neuregulin 4 (Nrg4), a member of the EGF family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat, and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3/ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR/SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat-enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and non-alcoholic fatty liver disease.

Summary A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic β cell failure, resulting in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining β cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We identify C3a, a peptide generated by adipsin, as a potent insulin secretagogue and show that the C3a receptor is required for these beneficial effects of adipsin. C3a acts on islets by augmenting ATP levels, respiration and cytosolic free Ca2+. Finally, we demonstrate that T2DM patients with β cell failure are deficient in adipsin. These findings indicate that the adipsin/C3a pathway connects adipocyte function to β cell physiology and manipulation of this molecular switch may serve as a novel therapy in T2DM.