https://www.cell.com/cell/pdf/S0092-8674(13)01546-8.pdf

What We Talk About When We Talk About Fat

Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis. Excitement surrounding this relatively recently identified hormone is based on the documented metabolic beneficial effects of FGF21, which include weight loss and improved glycemia. The biology of FGF21 is intrinsically complicated owing to its diverse metabolic functions in multiple target organs and its ability to act as an autocrine, paracrine, and endocrine factor. In the liver, FGF21 plays an important role in the regulation of fatty acid oxidation both in the fasted state and in mice consuming a high-fat, low-carbohydrate ketogenic diet. FGF21 also regulates fatty acid metabolism in mice consuming a diet that promotes hepatic lipotoxicity. In white adipose tissue (WAT), FGF21 regulates aspects of glucose metabolism, and in susceptible WAT depots, it can cause browning. This peptide is highly expressed in the pancreas, where it appears to play an anti-inflammatory role in e...

Understanding the Physiology of FGF21

Adipose tissue regulates numerous physiological processes, and its dysfunction in obese humans is associated with disrupted metabolic homeostasis, insulin resistance and type 2 diabetes mellitus (T2DM). Although several US-approved treatments for obesity and T2DM exist, these are limited by adverse effects and a lack of effective long-term glucose control. In this Review, we provide an overview of the role of adipose tissue in metabolic homeostasis and assess emerging novel therapeutic strategies targeting adipose tissue, including adipokine-based strategies, promotion of white adipose tissue beiging as well as reduction of inflammation and fibrosis.

Targeting adipose tissue in the treatment of obesity-associated diabetes

Non-alcoholic fatty liver disease - the most common chronic liver disease - encompasses a histological spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Over the next decade, NASH is projected to be the most common indication for liver transplantation. The absence of an effective pharmacological therapy for NASH is a major incentive for research into novel therapeutic approaches for this condition. The current focus areas for research include the modulation of nuclear transcription factors; agents that target lipotoxicity and oxidative stress; and the modulation of cellular energy homeostasis, metabolism and the inflammatory response. Strategies to enhance resolution of inflammation and fibrosis also show promise to reverse the advanced stages of liver disease.

Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies

The cause of insulin resistance in obesity and type 2 diabetes mellitus (T2DM) is not limited to impaired insulin signalling but also involves the complex interplay of multiple metabolic pathways. The analysis of large data sets generated by metabolomics and lipidomics has shed new light on the roles of metabolites such as lipids, amino acids and bile acids in modulating insulin sensitivity. Metabolites can regulate insulin sensitivity directly by modulating components of the insulin signalling pathway, such as insulin receptor substrates (IRSs) and AKT, and indirectly by altering the flux of substrates through multiple metabolic pathways, including lipogenesis, lipid oxidation, protein synthesis and degradation and hepatic gluconeogenesis. Moreover, the post-translational modification of proteins by metabolites and lipids, including acetylation and palmitoylation, can alter protein function. Furthermore, the role of the microbiota in regulating substrate metabolism and insulin sensitivity is unfolding. In this Review, we discuss the emerging roles of metabolites in the pathogenesis of insulin resistance and T2DM. A comprehensive understanding of the metabolic adaptations involved in insulin resistance may enable the identification of novel targets for improving insulin sensitivity and preventing, and treating, T2DM.

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Metabolites as regulators of insulin sensitivity and metabolism

Fibroblast growth factor 21 (FGF21) has multiple metabolic actions, including the induction of browning in white adipose tissue. Although FGF21 stimulated browning results from a direct interaction between FGF21 and the adipocyte, browning is typically associated with activation of the sympathetic nervous system through cold exposure. We tested the hypothesis that FGF21 can act via the brain, to increase sympathetic activity and induce browning, independent of cell-autonomous actions. We administered FGF21 into the central nervous system via lateral ventricle infusion into male mice and found that the central treatment increased norepinephrine turnover in target tissues that include the inguinal white adipose tissue and brown adipose tissue. Central FGF21 stimulated browning as assessed by histology, expression of uncoupling protein 1, and the induction of gene expression associated with browning. These effects were markedly attenuated when mice were treated with a β-blocker. Additionally, neither centrally nor peripherally administered FGF21 initiated browning in mice lacking β-adrenoceptors, demonstrating that an intact adrenergic system is necessary for FGF21 action. These data indicate that FGF21 can signal in the brain to activate the sympathetic nervous system and induce adipose tissue thermogenesis.

Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice.

Brown/beige adipocytes are therapeutic targets to combat obesity due to their abilities to dissipate energy through adaptive thermogenesis. Most studies investigating induction of brown/beige adipocytes were conducted in cold condition (e.g., 4°C); much is unknown about how the thermogenic program of brown/beige adipocytes is regulated in thermoneutral condition (e.g., 30°C), which is within the thermal comfort zone of human dwellings in daily life. Therefore, this study aims to characterize the thermogenic program of brown/beige adipocytes in mice housed under ambient (22°C) versus thermoneutral condition (30°C). Male mice raised at 22°C or 30°C were fed either chow diet or high‐fat (HF) diet for 20 weeks. Despite less food intake, chow‐fed mice housed at 30°C remained the same body weight compared to mice at 22°C. However, these thermoneutrally housed mice displayed a decrease in the expression of thermogenic program in both brown and white fat depots with larger adipocytes. When pair‐fed with chow diet, thermoneutrally housed mice showed an increase in body weight. Moreover, thermoneutrality increased body weight of mice fed with HF diet. This was associated with decreased expression of the thermogenic program in both brown and white fat depots of the thermoneutrally housed mice. The downregulation of the thermogenic program might have resulted from decreased sympathetic drive in the thermoneutrally housed mice evident by decreased expression of tyrosine hydroxylase expression and norepinephrine turnover in both brown and white fat depots. Our data demonstrate that thermoneutrality may negatively regulate the thermogenic program and sympathetic drive, leading to increased adiposity in mice.

Thermoneutrality decreases thermogenic program and promotes adiposity in high‐fat diet‐fed mice

There is a link between visceral white adipose tissue (WAT) and the metabolic syndrome in humans, with health improvements produced with small visceral WAT reduction. By contrast, subcutaneous WAT provides a site for lipid storage that is rather innocuous relative to ectopic lipid storage in muscle or liver. The sympathetic nervous system (SNS) is the principal initiator for lipolysis in WAT by mammals. Nothing is known, however, about the central origins of the SNS circuitry innervating the only true visceral WAT in rodents, mesenteric WAT (MWAT), which drains into the hepatic portal vein. We tested whether the central sympathetic circuits to subcutaneous [inguinal WAT (IWAT)] and visceral WAT (MWAT) are separate or shared and whether they possess differential sympathetic drives with food deprivation in Siberian hamsters. Using two isogenic strains of pseudorabies virus, a retrograde transneuronal viral tract tracer within the same hamsters, we found some overlap (∼20–55% doubly infected neurons) between the two circuitries across the neural axis with lesser overlap proximal to the depots (spinal cord and sympathetic chain) and with more neurons involved in the innervation of IWAT than MWAT in some brain regions. Food deprivation triggered a greater sympathetic drive to subcutaneous (IWAT) than visceral (MWAT) depots. Collectively, we demonstrated both shared and separate populations of brain, spinal cord, and sympathetic chain neurons ultimately project to a subcutaneous WAT depot (IWAT) and the only visceral WAT depot in rodents (MWAT). In addition, the lipolytic stimulus of food deprivation only increased SNS drive to subcutaneous fat (IWAT).

https://www.physiology.org/doi/pdf/10.1152/ajpregu.00552.2013

Central sympathetic innervations to visceral and subcutaneous white adipose tissue

Leptin, the primary white adipose tissue (WAT) adipokine, is thought to convey lipid reserve information to the brain via the circulation. Because WAT responds to environmental/internal signals in a fat pad-specific (FPS) manner, systemic signals such as leptin would fail to communicate such distinctive information. Saturation of brain leptin transport systems also would fail to convey increased lipid levels beyond that point. WAT possesses sensory innervation exemplified by proven sensory-associated peptides in nerves within the tissue and by viral sensory nerve-specific transneuronal tract tracer, H129 strain of herpes simplex virus 1 labeling of dorsal root ganglia (DRG) pseudounipolar neurons, spinal cord and central sensory circuits. Leptin as a paracrine factor activating WAT sensory innervation could supply the brain with FPS information. Therefore, we tested for and found the presence of the long form of the leptin receptor (Ob-Rb) on DRG pseudounipolar neurons immunohistochemically labeled after injections of Fluorogold, a retrograde tract tracer, into inguinal WAT (IWAT). Intra-IWAT leptin injections (300 ng) significantly elevated IWAT nerve spike rate within 5 min and persisted for at least 30 min. Intra-IWAT leptin injections also induced significant c-Fos immunoreactivity (ir), indicating neural activation across DRG pseudounipolar sensory neurons labeled with Fluorogold IWAT injections. Intraperitoneal leptin injection did not increase c-Fos-ir in DRG or the arcuate nucleus, nor did it increase arcuate signal transducer and activator of transcription 3 phosphorylation-ir. Collectively, these results strongly suggest that endogenous leptin secreted from white adipocytes functions as a paracrine factor to activate spinal sensory nerves innervating the tissue.

Leptin-sensitive sensory nerves innervate white fat

White adipose tissue (WAT) and brown adipose tissue (BAT) are innervated and regulated by the sympathetic nervous system (SNS). It is not clear, however, whether there are shared or separate centra...

https://www.physiology.org/doi/pdf/10.1152/ajpregu.00344.2016

Ngoc Ly T. Nguyen

Papers

Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice.

Thermoneutrality decreases thermogenic program and promotes adiposity in high‐fat diet‐fed mice

Central sympathetic innervations to visceral and subcutaneous white adipose tissue

Leptin-sensitive sensory nerves innervate white fat

Separate and shared sympathetic outflow to white and brown fat coordinately regulates thermoregulation and beige adipocyte recruitment.