Showing papers by "Bruce M. Spiegelman published in 2013"

Adaptive thermogenesis in adipocytes: Is beige the new brown?

Abstract: One of the most promising areas in the therapeutics for metabolic diseases centers around activation of the pathways of energy expenditure. Brown adipose tissue is a particularly appealing target for increasing energy expenditure, given its amazing capacity to transform chemical energy into heat. In addition to classical brown adipose tissue, the last few years have seen great advances in our understanding of inducible thermogenic adipose tissue, also referred to as beige fat. A deeper understanding of the molecular processes involved in the development and function of these cell types may lead to new therapeutics for obesity, diabetes, and other metabolic diseases.

Fat cells directly sense temperature to activate thermogenesis

Abstract: Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes. Cold is known to act indirectly through the sympathetic nervous systems and β-adrenergic signaling, but here we report that cool temperature (27–33 °C) can directly activate a thermogenic gene program in adipocytes in a cell-autonomous manner. White and beige fat cells respond to cool temperatures, but classic brown fat cells do not. Importantly, this activation in isolated cells is independent of the canonical cAMP/Protein Kinase A/cAMP response element-binding protein pathway downstream of the β-adrenergic receptors. These findings provide an unusual insight into the role of adipose tissues in thermoregulation, as well as an alternative way to target nonshivering thermogenesis for treatment of obesity and metabolic diseases.

Banting Lecture 2012: Regulation of adipogenesis: toward new therapeutics for metabolic disease.

Abstract: The Banting Medal for Scientific Achievement Award is the American Diabetes Association's highest scientific award and honors an individual who has made significant, long-term contributions to the understanding of diabetes, its treatment, and/or prevention.The award is named after Nobel Prize winner Sir Frederick Banting, who codiscovered insulin treatment for diabetes. Bruce M. Spiegelman, PhD, of Harvard Medical School and the Dana-Farber Cancer Institute in Boston, received the American Diabetes Association's Banting Medal for Scientific Achievement at the Association's 72nd Scientific Sessions, 8-12 June 2012, Philadelphia, Pennsylvania. He presented the Banting Lecture, "Transcriptional Control of Adipogenesis-Toward a New Generation of Therapeutics for Metabolic Disease," on Sunday, 10 June 2012. In his lecture, Dr. Spiegelman described the discovery of several transcriptional components that control adipose cell development: PPAR-γ, PGC1-α, and PRDM16. He also described the cloning and characterization of beige fat cells, the thermogenic "brown-like" cells that can develop in white fat depots. Lastly, Dr. Spiegelman discussed irisin, a newly discovered regulatory hormone that converts white fat into the more thermogenic beige fat. Dr. Spiegelman's research has found that irisin, which is induced by exercise, appears to activate some of the same health benefits as exercise, including improvement of glycemic control. Understanding the regulation of adipose tissue, white, brown, and beige, can potentially lead to the development of a new generation of therapeutics for diabetes prevention and treatment.

The protein level of PGC-1α, a key metabolic regulator, is controlled by NADH-NQO1.

Abstract: PGC-1α is a key transcription coactivator regulating energy metabolism in a tissue-specific manner. PGC-1α expression is tightly regulated, it is a highly labile protein, and it interacts with various proteins--the known attributes of intrinsically disordered proteins (IDPs). In this study, we characterize PGC-1α as an IDP and demonstrate that it is susceptible to 20S proteasomal degradation by default. We further demonstrate that PGC-1α degradation is inhibited by NQO1, a 20S gatekeeper protein. NQO1 binds and protects PGC-1α from degradation in an NADH-dependent manner. Using different cellular physiological settings, we also demonstrate that NQO1-mediated PGC-1α protection plays an important role in controlling both basal and physiologically induced PGC-1α protein level and activity. Our findings link NQO1, a cellular redox sensor, to the metabolite-sensing network that tunes PGC-1α expression and activity in regulating energy metabolism.

Potent Anti-Diabetic Actions of a Novel Non-Agonist PPARγ Ligand that Blocks Cdk5-Mediated Phosphorylation

Abstract: The incidence of diabetes is increasing rapidly as the percentage of the population ages and becomes more obese. According to the National Center for Health Statistics diabetes is now the sixth leading cause of death in the US. The biguanide metformin is typically the first-line medication used for treatment of type 2 diabetes mellitus (T2DM) as safety concerns over the use of the thiazolidinedione class [(TZD); rosiglitazone (Avandia) and pioglitazone (Actos) [1]] of insulin sensitizers has grown. This is unfortunate as TZDs have consistently shown robust efficacy for treatment of T2DM. TZDs target the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and are classified as full agonists. While weight gain is associated with use of TZDs, the major safety concerns include edema, plasma volume expansion (PVE or hemodilution) which is likely linked to cardiomegaly and increased risk of congestive heart failure, and an increased risk of bone fractures. The latter risk is most troublesome as detection is typically only made when a patient suffers a fracture. Studies in animal models and in clinical trials have shown that indicators of weight gain and PVE, while not eliminated, can be minimized without loss of insulin sensitization by the use of modulators that are weak or partial agonists of PPARγ (e.g., minimal agonism of the receptor as compared to TZDs). Partial agonists have been referred to as selective PPARγ modulators or SPPARγMs and this class of ligand has been shown to have a different binding mode in the PPARγ ligand binding pocket (LBP) as compared to the full agonists [2]. Selective recruitment of transcriptional coactivators by partial agonists has also been demonstrated. A combination of different ligand binding mode and distinct coactivator recruitment profile may explain the change in gene expression patterns compared to that of full agonists [3]. While it is unclear if the bone fracture risk has been minimized with use of such agents, these studies clearly demonstrate that the anti-diabetic efficacy of partial agonists is uncoupled from their transcriptional activity but does correlate well with binding potency. Recently we have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5. Due to their improved adverse event profile of partial agonists and the observation of separate biochemical activities of PPARγ ligands, we sought to develop compounds with high affinity binding to PPARγ but that lacked classical agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Here we describe one such compound, ML244, which has a unique mode of binding to PPARγ, has potent anti-diabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, ML244 does not interfere with bone formation in culture. These data illustrate that new classes of anti-diabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ.