A role for central nervous system PPAR-γ in the regulation of energy balance

Ryan, Karen K.; Li, Bailing; Grayson, Bernadette E.; Matter, Emily K.; Woods, Stephen C.; Seeley, Randy J.

doi:10.1038/nm.2349

Cited by 197 publications

(206 citation statements)

References 30 publications

Supporting

Mentioning

186

Contrasting

Unclassified

Order By: Relevance

“…It is intriguing to note, however, that hypophagia can be turned into hyperphagia upon treatment of AKO/cTg mice with the synthetic PPAR-γ agonist rosiglitazone, suggesting a function of PPAR-γ in appetite regulation. In support of this concept, several recent studies underscored the importance of PPAR-γ in the brain for the regulation of food intake (20,21). Because AKO/cTg mice lack ATGL in the brain, it is conceivable that central ATGL deficiency impairs PPAR-γ signaling in the brain, leading to reduced food intake.…”

Section: Discussionmentioning

confidence: 98%

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Schreiber

Hofer

Taschler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride (TG) catabolism. In humans, ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM) characterized by a systemic TG accumulation. Mice with a genetic deletion of ATGL (AKO) also accumulate TG in many tissues. However, neither NLSDM patients nor AKO mice are exceedingly obese. This phenotype is unexpected considering the importance of the enzyme for TG catabolism in white adipose tissue (WAT). In this study, we identified the counteracting mechanisms that prevent excessive obesity in the absence of ATGL. We used "healthy" AKO mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to circumvent the cardiomyopathy and premature lethality observed in AKO mice. AKO/cTg mice were protected from high-fat diet (HFD)-induced obesity despite complete ATGL deficiency in WAT and normal adipocyte differentiation. AKO/cTg mice were highly insulin sensitive under hyperinsulinemic-euglycemic clamp conditions, eliminating insulin insensitivity as a possible protective mechanism. Instead, reduced food intake and altered signaling by peroxisome proliferator-activated receptor-gamma (PPAR-γ) and sterol regulatory element binding protein-1c in WAT accounted for the phenotype. These adaptations led to reduced lipid synthesis and storage in WAT of HFD-fed AKO/cTg mice. Treatment with the PPAR-γ agonist rosiglitazone reversed the phenotype. These results argue for the existence of an adaptive interdependence between lipolysis and lipid synthesis. Pharmacological inhibition of ATGL may prove useful to prevent HFDinduced obesity and insulin resistance.E ssentially all organisms face the problem of continuous energy demand in an environment of irregular food supply. To overcome this dilemma, metazoan organisms developed special storage depots for substrates that are used for energy production. In vertebrates, by far the most efficient energy reservoir is adipose tissue (1). This highly expandable organ is able to store all major nutritional components (fat, carbohydrates, and proteins) as triglycerides (TGs). Adipose tissue mass and TG content depend on the balance of anabolic and catabolic pathways. Lipid storage in response to nutrient supply involves the generation of adipocytes (adipogenesis), the induction of fatty acid (FA) synthesis from glucose and amino acids (de novo lipogenesis), and the synthesis of TGs (lipid synthesis). These processes are activated by a complex transcriptional network involving CCAAT/ enhancer-binding proteins (C/EBPs), sterol regulatory enhancer binding proteins (SREBPs), and the heterodimer of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and retinoid-X receptor (RXR) (2, 3).The opposing metabolic pathway of TG catabolism (lipolysis) requires activation of enzymes called lipases. Adipose TG lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) hydrolyze all three ester bonds of TGs in a stepwise manner to yield FAs and glycerol (4). Lipolysis is an exquisitely regulated proce...

show abstract

Section: Discussionmentioning

confidence: 98%

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Schreiber

Hofer

Taschler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Several studies, including our own, have suggested a central role for PPARγ in whole-body energy homeostasis (3)(4)(5)(6)(7). Hypothalamic Pparg mRNA expression is several folds higher compared with Ppara or Ppard mRNA expression, and Pparg mRNA expression increases significantly in diet-induced obese (DIO) mice when compared with that of lean controls (7).…”

Section: Introductionmentioning

confidence: 90%

“…Hypothalamic Pparg mRNA expression is several folds higher compared with Ppara or Ppard mRNA expression, and Pparg mRNA expression increases significantly in diet-induced obese (DIO) mice when compared with that of lean controls (7). While brain-specific deletion of PPARγ decreased food intake and increased energy expenditure (EE) in DIO mice (6), chronic hypothalamic-specific PPARγ activation induced increased food intake and body weight in DIO mice (5). In addition, deletion of PPARγ in the brain or in the hypothalamus conferred resistance to rosiglitazone-induced food intake and body weight gain (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…While brain-specific deletion of PPARγ decreased food intake and increased energy expenditure (EE) in DIO mice (6), chronic hypothalamic-specific PPARγ activation induced increased food intake and body weight in DIO mice (5). In addition, deletion of PPARγ in the brain or in the hypothalamus conferred resistance to rosiglitazone-induced food intake and body weight gain (5,6). Nevertheless, the identity of PPARγ-expressing neurons and the mode of action on cellular mechanisms in these cells that mediate the effect of PPAR agonists on energy homeostasis remains elusive.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding

Long¹,

Toda²,

Jeong³

et al. 2014

J. Clin. Invest.

View full text Add to dashboard Cite

Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.

show abstract

“…Thiazolidinediones (TZDs), including rosiglitazone, are PPARγ agonists and many varieties are currently used as anti-diabetic drugs as they reduce insulin resistance and blood glucose levels in patients with T2D [196]. Interestingly, patients receiving such drugs were also protected from neurodegenerative pathologies.…”

Section: Peroxisome Proliferator-activated Receptorsmentioning

confidence: 99%

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

Lomis¹

2015

J Diabetes Metab

View full text Add to dashboard Cite

The gut microflora is a community of trillions of bacterial cells synergistically inhabiting the human gastrointestinal tract. These microbes contact everything that is consumed and release regulatory factors that affect host energy homeostasis, lipid and carbohydrate metabolism, activation of immune cells, oxidative state, epithelial cell wall integrity and even neurological signals. The gut microflora is essentially an independent organ supporting human health where imbalances in the gut community populations (dysbiosis) manifest in disease. Diabetes and neurodegenerative disorders such as Alzheimer's and Parkinson's disease share a similar molecular pathology rooted in gut microflora activity. Both of these conditions are associated with a dysbiosis characterized by low species diversity, a higher proportion of pathobionts at the expense of symbionts, an abundance of proinflammatory microbes and fewer butyrate-producing strains. Many of these factors can be ameliorated with Lactobacillus spp. and Bifidobacterium spp. probiotic treatment aimed to reestablish healthy gut microflora diversity. Indeed, certain commensal and pathogenic strains promote chronic low-grade inflammation that stresses cellular infrastructure eventually leading to apoptosis in both the pancreas and the brain. Also, lack of some beneficial fermentation products such as butyrate and ferulic acid initiates a cascade of events disrupting metabolic homeostasis. Finally, signaling initiated by the microflora and its metabolites has been shown to disrupt the delicate intracellular balance of PI3K/Akt/mTOR signaling, which fundamentally regulates events leading up to diabetes and neurodegenerative disease pathogenesis. The following review investigates the relationship between the manifestation and molecular signaling of diabetes and neurodegenerative disorders and how the balance of gut microflora populations is critical to both prevent and possibly treat these diseases.

show abstract

A role for central nervous system PPAR-γ in the regulation of energy balance

Cited by 197 publications

References 30 publications

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

Contact Info

Product

Resources

About