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.

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In this study, we extend previous work on iron deficiency and dopamine (DA) transporters to include an examination of central serotonin (5-HT) and noradrenergic (NE) transporters. Rats were fed either iron deficient (ID) or iron adequate (CN) diets from weaning until adulthood. In males, an additional group of iron deficient animals (IR) were given iron supplementation. DA, 5-HT, and NE transporter binding was done in situ on thin sections. ID males, but not females, decreased DA transporter binding in the nucleus accumbens, caudate putamen and substantia nigra by 20-40%. ID males also had a 20-30% reduction in 5-HT transporter binding in several areas (nucleus accumbens, olfactory tubercle, colliculus) while in ID females there was 15-25% increased serotonin transporter binding in the olfactory tubercle, zona incerta, anteroventral thalamic nucleus and vestibular nucleus. Iron deficiency reduced 3H-nisoxetine binding to the NE transporter in locus ceruleus and anteroventral thalamic nucleus in males but not females. Only some of the changes observed in DA, serotonin and NE transporter binding were reversible by iron supplementation. These findings show that iron deficiency affects monoamine systems related to homeostasis and in most cases males appear to be more vulnerable than females.

SummaryAdipose tissue expansion has been associated with system‐wide metabolic dysfunction and increased vulnerability to diabetes, cancer, and cardiovascular disease. A reduction in adiposity is a hallmark of caloric restriction (CR), an intervention that extends longevity and delays the onset of these same age‐related conditions. Despite these parallels, the role of adipose tissue in coordinating the metabolism of aging is poorly defined. Here, we show that adipose tissue metabolism and secretory profiles change with age and are responsive to CR. We conducted a cross‐sectional study of CR in adult, late‐middle‐aged, and advanced‐aged mice. Adiposity and the relationship between adiposity and circulating levels of the adipose‐derived peptide hormone adiponectin were age‐sensitive. CR impacted adiposity but only levels of the high molecular weight isoform of adiponectin responded to CR. Activators of metabolism including PGC‐1a, SIRT1, and NAMPT were differentially expressed with CR in adipose tissues. Although age had a significant impact on NAD metabolism, as detected by biochemical assay and multiphoton imaging, the impact of CR was subtle and related to differences in reliance on oxidative metabolism. The impact of age on circulating lipids was limited to composition of circulating phospholipids. In contrast, the impact of CR was detected in all lipid classes regardless of age, suggesting a profound difference in lipid metabolism. These data demonstrate that aspects of adipose tissue metabolism are life phase specific and that CR is associated with a distinct metabolic state, suggesting that adipose tissue signaling presents a suitable target for interventions to delay aging.

Caloric restriction (CR) extends lifespan and delays the onset of age-related disorders in diverse species. Metabolic regulatory pathways have been implicated in the mechanisms of CR, but the molecular details have not been elucidated. Here, we show that CR engages RNA processing of genes associated with a highly integrated reprogramming of hepatic metabolism. We conducted molecular profiling of liver biopsies collected from adult male rhesus monkeys (Macaca mulatta) at baseline and after 2 years on control or CR (30% restricted) diet. Quantitation of over 20,000 molecules from the hepatic transcriptome, proteome, and metabolome indicated that metabolism and RNA processing are major features of the response to CR. Predictive models identified lipid, branched-chain amino acid, and short-chain carbon metabolic pathways, with alternate transcript use for over half of the genes in the CR network. We conclude that RNA-based mechanisms are central to the CR response and integral in metabolic reprogramming.

AT-1/SLC33A1 is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation. Dysfunctional ER acetylation, as caused by heterozygous or homozygous mutations as well as gene duplication events of AT-1/SLC33A1 , has been linked to both developmental and degenerative diseases. Here, we investigate two models of AT-1 dysregulation and altered acetyl-CoA flux: AT-1 S113R/+ mice, a model of AT-1 haploinsufficiency, and AT-1 sTg mice, a model of AT-1 overexpression. The animals display distinct metabolic adaptation across intracellular compartments, including reprogramming of lipid metabolism and mitochondria bioenergetics. Mechanistically, the perturbations to AT-1-dependent acetyl-CoA flux result in global and specific changes in both the proteome and the acetyl-proteome (protein acetylation). Collectively, our results suggest that AT-1 acts as an important metabolic regulator that maintains acetyl-CoA homeostasis by promoting functional crosstalk between different intracellular organelles.

This article is available online at http://www.jlr.orgRecently, the prevalence of overweight among all adults in the US was estimated to be nearly 70% ( 1 ), and has increased more than 2-fold since 1980 ( 2 ). With increased adiposity, lipids accumulate ectopically and are associated with increased risk for detrimental metabolic conditions such as nonalcoholic fatty liver disease, insulin resistance, and hypertriglyceridemia ( 3-5 ). The balance of lipid storage between liver and adipose depots may play an important role in disease vulnerability. Fat may be synthesized from dietary carbohydrates via de novo lipogenesis (DNL), or sequestered from circulating lipids. The contribution of hepatic and adipose tissue DNL-derived fat to wholebody adiposity is controversial. While it is considered to be quantitatively minimal by some ( 6, 7 ), others have demonstrated that DNL-derived lipids can negatively impact metabolic health and contribute to hepatic steatosis and visceral adiposity in humans ( 8-10 ). Of particular importance in the context of whole-body metabolic homeostasis, recent evidence suggests that de novo synthesized fatty acids and lipids serve important signaling and regulatory roles in cellular and systemic metabolism ( 7,11 ).MUFAs are major components of tissue lipids such as TGs, cholesteryl esters (CEs), and GPs , and high levels of MUFAs are inversely associated with metabolic health. The stearoyl-CoA desaturase (SCD) family of enzymes catalyzes the synthesis of MUFAs by insertion of a cis double bond at the ⌬ 9 position of saturated fatty acids. DK062388, ADA 7-13-BS-118, and USDA Hatch W2005 (to J.M.N.), and NIH Grant RO1 AG037000 (to R.M.A.) Abbreviations: ASM, acid soluble metabolite; CE, cholesteryl ester; DNL, de novo lipogenesis; GKO, stearoyl-CoA desaturase 1 global knockout; GLC, gas liquid chromatography; GLS5, global knockout liver-specifi c stearoyl-CoA desaturase 5 transgenic; GLS3, global knockout liver-specifi c stearoyl-CoA desaturase 3 transgenic; LD, lipogenic diet; LKO, stearoyl-CoA desaturase 1 liver knockout; SCD, stearoyl-CoA desaturase; WAT, white adipose tissue .1 To whom correspondence should be addressed. e-mail: jmntambi@wisc.edu The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three fi gures and nine tables. METHODS Animals and dietsTwo liver transgenic mouse lines were generated by cloning either the human SCD5 cDNA sequence or the mouse SCD3 cDNA sequence into the pLiv.LE6 vector construct (a kind gift from John Taylor, Gladstone Institute) ( 20 ). Mice were backcrossed at least seven generations with C57BL/6 mice to generate SCD5Tg+ and SCD3Tg+ mice. SCD5Tg+ and SCD3Tg+ mice were then crossed with SCD1 GKO mice (in C57BL/6 background) to generate compound heterozygous mice, SCD1+/ Ϫ carrying one copy of the SCD5 or SCD3 transgene. These compound heterozygous mice were then bred with female SCD1+/ Ϫ or male SCD1 Ϫ / Ϫ mice to generate SCD5Tg+;SCD1 Ϫ / Ϫ (GLS5) and SCD3Tg+;SCD1 Ϫ / Ϫ (GLS3) mice.Mice wer...

Background & Aims High-carbohydrate diets contribute to the development of liver stress and fatty liver disease. While saturated fatty acids are known to induce liver stress, the role of monounsaturated fatty acids (MUFA), synthesized by the stearoyl-CoA desaturase (SCD) family of enzymes, in regulation of liver function during lipogenic dietary conditions remains largely unknown. The major products of SCD-catalyzed reactions are oleate (18:1n-9) and palmitoleate (16:1n-7). Methods We generated mouse models with restricted exogenous MUFA supply and reduced endogenous MUFA synthesis, in which SCD1 global knockout (GKO) or liver-specific knockout (LKO) mice were fed a lipogenic high-sucrose very low-fat (HSVLF) or high-carbohydrate (HC) diet. In a gain-of-function context, we introduced liver-specific expression of either human SCD5, which synthesizes 18:1n-9, or mouse Scd3, which synthesizes 16:1n-7, into SCD1 GKO mice and fed the HSVLF diet. Results Lipogenic high-carbohydrate diets induced hepatic endoplasmic reticulum (ER) stress and inflammation in SCD1 GKO and LKO mice. Dietary supplementation with 18:1n-9, but not 18:0, prevented the HSVLF diet-induced hepatic ER stress and inflammation in SCD1 LKO mice, while hepatic SCD5, but not Scd3, expression reduced the ER stress and inflammation in GKO mice. Additional experiments revealed liver-specific deletion of the transcriptional coactivator PGC-1α reduced hepatic inflammatory and ER stress response gene expression in SCD1 LKO mice. Conclusions Our results demonstrate an indispensable role of hepatic oleate in protection against lipogenic diet-induced hepatic injury, and PGC-1α potentiates the ER stress response under conditions of restricted dietary oleate coupled to reduced capacity of endogenous hepatic oleate synthesis.