Our Favorite Papers of 2016
Every year we like to come up with some of the papers we really enjoyed reading this year during our journal club (see here for last year's papers). Here are some of our favorites from this year
Modulation of Energy Expenditure
- Liu D, Bordicchia M, Zhang C, Fang H, Wei W, Li J-L, Guilherme A, Guntur K, Czech MP, Collins S. Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning. J Clin Invest. 2016; 126: 1704–16. doi: 10.1172/JCI83532.
This paper from Sheila Collins's lab at Sanford Burhnam Prebys Medical Discovery Institute showed that adrenergic stimuli, including cold stress can activate mTORC1 (in addition to the better known anabolic stimuli such as growth factors, amino acids and AMPK inhibition) in adipose tissue. but then showed that adipose mTORC1 activity is essential for maintaining thermal stability upon cold stress. This highlights the important role of mTORC1 not only in anabolic, but also in catabolic responses to over-nutrition - Dave.
- Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MRR, Jedrychowski MP, Paulo JA, Gygi SP, Griffin PR, et al. The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria. Cell. 2016; 166: 424–35. doi: 10.1016/j.cell.2016.05.071.
Towards the end of the calendar year, this paper led by Bruce Spiegelman's group at Harvard Medical School identified a surprising factor secreted from brown adipose tissue (PM20D1) that causes the generation of acylated amino acids. These acylated amino acids (particularly C18:1-Leu or Phe) increased energy expenditure in cultured muscle and adipose cells as well as in mice - Dave.
- Kim HJ, Cha JY, Seok JW, Choi Y, Yoon BK, Choi H, Yu JH, Song SJ, Kim A, Lee H, Kim D, Han JY, Kim J. Dexras1 links glucocorticoids to insulin-like growth factor-1 signaling in adipogenesis. Sci Rep. Nature Publishing Group; 2016; 6: 28648. doi: 10.1038/srep28648.
Kim et al. found that Dexras1, a glucocorticoid receptor target (confirmed by ChIP), is required for insulin-induced p-ERK signaling during differentiation of 3T3-L1 adipocytes. This happens via insulin signaling through the IGF-1 receptor, along with chaperone proteins, allowing for translocation of Dexras1 to the plasma membrane. The process is blocked when the protein is mutated or when the IGF-1 receptor is silenced - Innocence.
- Mueller KM, Hartmann K, Kaltenecker D, Vettorazzi S, Bauer M, Mauser L, Amann S, Jall S, Fischer K, Esterbauer H, Müller TD, Tschöp MH, Magnes C, et al. Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and Hfd-Induced Obesity, and Impairs the Feeding-Fasting Transition. Diabetes. 2016; : db160381. doi: 10.2337/db16-0381.
In this article Mueller and colleagues investigate the role of the glucocorticoid receptor in adipose tissue (using adipose tissue specific GR KO mice) in the development of insulin resistance and fatty liver under a multitude of circumstances such as aging, HFD-induced obesity and prolonged fasting. The overall findings indicate that ablation of the GR solely in adipose tissue results in enhanced insulin sensitivity, decreased lipolysis, decreased subcutaneous and visceral fat mass and cell volume and prevents liver steatosis - Innocence.
- Marino JS, Stechschulte LA, Stec DE, Nestor-Kalinoski A, Coleman S, Hinds TD. Glucocorticoid receptor β induces hepatic steatosis by augmenting inflammation and inhibition of the peroxisome proliferator-activated receptor (PPAR) α. J Biol Chem. 2016; 291: 9383–94. doi: 10.1074/jbc.M116.752311.
Marino and associates studied the relationship between GRβ and hepatic steatosis and found that GRβ is increased in mouse liver and adipose tissue, but not muscle in response to HFD. Overexpression of GRβ in the liver led to enhanced FASN and pro-inflammatory markers paired with reductions in anti-inflammatory markers, PTEN (low levels of this protein have been associated with the development of NASH) and PPARy promoter activity. The authors state that enhanced GRβ leads to liver steatosis via increased hepatic lipid accumulation and decreased β-oxidation and suggest that prolonged elevations of GRβ may lead to further progression of liver disease - Innocence.
- Stemmer K, Zani F, Habegger KM, Neff C, Kotzbeck P, Bauer M, Yalamanchilli S, Azad A, Lehti M, Martins PJF, Müller TD, Pfluger PT, Seeley RJ. FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice. Diabetologia. 2015; 58: 2414–23. doi: 10.1007/s00125-015-3668-7.
In this article, Seeley and colleagues examined the role of Fibroblast Growth Factor 21 (FGF21) in mediating the beneficial aspects of Ketogenic Diets on metabolism and cancer (using Fgf21 knockout mice). Their findings suggest that endogenous FGF21 is not needed for the known effects of a Ketogenic Diet on energy expenditure because of the maintenance of normoglycemia upon carbohydrate starvation. They also found that FGF21 is not necessary for tumor-suppression, which is potentially driven by carbohydrate and protein starvation. These findings are intriguing as FGF21 has always been thought of as essential for ketogenic regulation and for mediating many of the benefits associated with ketogenic diets. - Cody
- Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Müller CP, Tang H, et al. FGF21 regulates sweet and alcohol preference. Cell Metab. 2016; 23: 344–9. doi: 10.1016/j.cmet.2015.12.008.
The authors of this study studied effects of FGF21 on nutrient preferences and reward behavior. They first gave wild-type and FGF21 mice two-bottle preference tests with 3%sucrose versus water and 0.2%sacchrin versus water. In both cases, the FGF21 mice consumed less of the sweetened water. They then gave mice with and without -Klotho, an FGF21 co-receptor, FGF21or vehicle and two-bottle tested them. When treated with FGF21, mice with -Klotho drank significantly less sweetened water. -Klotho knockout mice consumed the same amount of sweetened water regardless of whether or not they were treated with FGF21. There was no difference in the consumption of quinine by either group, suggesting that FGF21 does not affect fat or bitter tastes. They injected obese mice and monkeys with an FGF21 analog and saw a decrease in sweetened water preference. Because FGF21 affects the dopamine pathway, researchers looked at dopamine in the brains of the FGF21 mice and saw that it was down regulated. Because dopamine signaling affects ethanol drinking, researchers looked at whether FGF21 effects alcohol preference. When given the two-bottle test, FGF21 mice exhibited a decreased preference for ethanol - JeAnna.
Regulation of Lipid Metabolism
- Kim M-S, Krawczyk SA, Doridot L, Fowler AJ, Wang JX, Trauger SA, Noh H, Kang HJ, Meissen JK, Blatnik M, Kim JK, Lai M, Herman MA. ChREBP regulates fructose-induced glucose production independently of insulin signaling. J Clin Invest. 2016; 126: 4372–86. doi: 10.1172/JCI81993.
This paper from Mark Herman's group at Beth Israel Deaconess Medical Center showed the dramatic responses of ChREBP to fructose, and how glucoregulatory responses to both a fructose and a glucagon challenge are ablated in ChREBP knockouts. They then show that fructose-induced activation of ChREBP targets are independent of insulin signaling. These studies are consistent with a model in which fructose exacerbates hyperglycemia and de novo lipogenesis, independent of hyperinsulinemia - Dave.
- Cropley JE, Eaton SA, Aiken A, Young PE, Giannoulatou E, Ho JWK, Buckland ME, Keam SP, Hutvagner G, Humphreys DT, Langley KG, Henstridge DC, Martin DIK, et al. Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity. Mol Metab. 2016; 5(8): 699-708. doi: 10.1016/j.molmet.2016.06.008.
This study design is unique because it evaluates males in the transmission of an acquired trait instead of females, which has been more extensively studied. It was found that worsened metabolic outcomes persisted through the F3 generation. These deleterious effects were seen only after exposure to western diet. Males with a father or grandfather who suffered from obesity may have the ability to pass down to their offspring a greater risk of metabolic illness, even if they are lean and healthy - Molly.
- Srinivasan M, Dodds C, Ghanim H, Gao T, Ross PJ, Browne RW, Dandona P, Patel MS. Maternal obesity and fetal programming: effects of a high-carbohydrate nutritional modification in the immediate postnatal life of female rats. Am J Physiol Endocrinol Metab. 2008; 295: E895-903. doi: 10.1152/ajpendo.90460.2008.
This study evaluates high carbohydrate and maternal obesity on metabolic outcomes of the offspring. The researchers also aimed to separate origin of the egg from the intrauterine environment by completing embryo transfer studies. This study suggests that intrauterine environment and inflammation due to maternal obesity may be one of the mechanisms that predispose offspring to hyperphagia and poor metabolic health - Molly.
- Masuyama H, Mitsui T, Eguchi T, Tamada S, Hiramatsu Y. The effects of paternal high-fat diet exposure on offspring metabolism with epigenetic changes in the mouse adiponectin and leptin gene promoters. Am J Physiol - Endocrinol Metab. 2016; 311: E236–45. doi: 10.1152/ajpendo.00095.2016.
This study is interesting because it focuses on the effects of paternal diet rather than maternal, as maternal effects are studied often, on offspring metabolic-like syndrome. It’s a large study that spans several generations of animals on different combinations of control and high-fat diets. Male and female mice were given control or high-fat diets and mated with mice given the same or opposite diet. Researchers found that paternal diet had an effect on the body weight, body weight/fat mass ratio, insulin resistance, serum triglycerides, leptin, adiponectin, and systolic blood pressure independent of and synergistic to maternal diet effects. They then put offspring on control diet over three generations and observed that these phenotypes could be reversed over time - JeAnna.