Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is ...an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.
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•5/6 nephrectomy and LLC tumors trigger cachexia and adipose tissue browning•Elevated circulating PTH and PTHrP stimulate browning through their receptor PTHR•PTHR function in fat is required for adipose tissue browning and wasting•Loss of PTHR in fat tissue also attenuates skeletal muscle atrophy
Kir et al. reveal a role for the PTH/PTHrP pathway in cachexia driven by kidney failure or cancer and show how PTH and PTHrP stimulate adipose tissue browning through their receptor PTHR. Loss of PTHR in adipocytes blocks atrophy of not only fat tissue, but also skeletal muscle in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exercise provides many health benefits, including improved metabolism, cardiovascular health, and cognition. We have shown previously that FNDC5, a type I transmembrane protein, and its circulating ...form, irisin, convey some of these benefits in mice. However, recent reports questioned the existence of circulating human irisin both because human FNDC5 has a non-canonical ATA translation start and because of claims that many human irisin antibodies used in commercial ELISA kits lack required specificity. In this paper we have identified and quantitated human irisin in plasma using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. This precise state-of-the-art method shows that human irisin is mainly translated from its non-canonical start codon and circulates at ∼3.6 ng/ml in sedentary individuals; this level is increased to ∼4.3 ng/ml in individuals undergoing aerobic interval training. These data unequivocally demonstrate that human irisin exists, circulates, and is regulated by exercise.
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•Detection and quantitation of human plasma irisin by quantitative mass spectrometry•Irisin is mainly translated from its non-canonical start codon•Irisin circulates at ∼3.6 ng/ml in sedentary individuals•Irisin levels significantly increase in individuals undergoing aerobic training
Irisin is an exercise-induced myokine with beneficial metabolic functions. Its detection in human plasma has, however, been problematic. Here, Jedrychowski et al. use state-of-the-art quantitative mass spectrometry to precisely detect and quantify circulating irisin and show that it goes up in individuals undergoing aerobic interval training.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exercise induces physiological cardiac growth and protects the heart against pathological remodeling. Recent work suggests exercise also enhances the heart’s capacity for repair, which could be ...important for regenerative therapies. While microRNAs are important in certain cardiac pathologies, less is known about their functional roles in exercise-induced cardiac phenotypes. We profiled cardiac microRNA expression in two distinct models of exercise and found microRNA-222 (miR-222) was upregulated in both. Downstream miR-222 targets modulating cardiomyocyte phenotypes were identified, including HIPK1 and HMBOX1. Inhibition of miR-222 in vivo completely blocked cardiac and cardiomyocyte growth in response to exercise while reducing markers of cardiomyocyte proliferation. Importantly, mice with inducible cardiomyocyte miR-222 expression were resistant to adverse cardiac remodeling and dysfunction after ischemic injury. These studies implicate miR-222 as necessary for exercise-induced cardiomyocyte growth and proliferation in the adult mammalian heart and show that it is sufficient to protect the heart against adverse remodeling.
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•MicroRNAs concordantly regulated by distinct forms of exercise were identified•miR-222 induces cellular hypertrophy and proliferation in vitro via distinct targets•Inhibition of miR-222 in vivo completely blocks exercise-induced cardiac growth•Cardiac expression of miR-222 reduces adverse remodeling after ischemic injury
Exercise has many cardiovascular benefits that are only partly understood. Liu et al. identify miR-222, together with its targets p27, HIPK1, and HMBOX1, as an important mediator of exercise-induced cardiac growth. Cardiac expression of miR-222 also protects against adverse remodeling and cardiac dysfunction after ischemic injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Deconvoluting the natural pathway of BAT development has defined key molecular events, which enables researchers to manipulate the amount or activity of brown fat. We review recent advances on the ...transcriptional regulation of BAT development and discuss the emerging questions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thermogenic UCP1-positive cells, which include brown and beige adipocytes, transform chemical energy into heat and increase whole-body energy expenditure. Using a ribosomal profiling approach, we ...present a comprehensive molecular description of brown and beige gene expression from multiple fat depots in vivo. This UCP1-TRAP data set demonstrates striking similarities and important differences between these cell types, including a smooth muscle-like signature expressed by beige, but not classical brown, adipocytes. In vivo fate mapping using either a constitutive or an inducible Myh11-driven Cre demonstrates that at least a subset of beige cells arise from a smooth muscle-like origin. Finally, ectopic expression of PRDM16 converts bona fide vascular smooth muscle cells into Ucp1-positive adipocytes in vitro. These results establish a portrait of brown and beige adipocyte gene expression in vivo and identify a smooth muscle-like origin for beige cells.
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•Ribosomal profiling provides a molecular portrait of thermogenic adipocytes in vivo•Beige, but not classical brown cells, express smooth muscle-like genes•Smooth muscle-like cells are precursors for beige adipocytes in vivo•PRDM16 converts smooth muscle cells into thermogenic adipocytes in vitro
Long et al. use ribosomal profiling (TRAP) to analyze UCP1-positive cells and map similarities and differences between brown and beige adipocytes, including a “smooth muscle-like” signature for beige but not brown adipocytes. In vivo fate mapping reveal a smooth muscle-like origin for beige cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exercise can improve cognitive function and has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation ...of this neurotrophin remain unknown. Here we show that FNDC5, a previously identified muscle protein that is induced in exercise and is cleaved and secreted as irisin, is also elevated by endurance exercise in the hippocampus of mice. Neuronal Fndc5 gene expression is regulated by PGC-1α, and Pgc1a−/− mice show reduced Fndc5 expression in the brain. Forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, whereas RNAi-mediated knockdown of FNDC5 reduces Bdnf. Importantly, peripheral delivery of FNDC5 to the liver via adenoviral vectors, resulting in elevated blood irisin, induces expression of Bdnf and other neuroprotective genes in the hippocampus. Taken together, our findings link endurance exercise and the important metabolic mediators, PGC-1α and FNDC5, with BDNF expression in the brain.
•Exercise induces FNDC5 in the hippocampus•PGC-1α regulates neuronal Fndc5 gene expression in vitro and in vivo•FNDC5 positively regulates the expression of the important neurotrophin BDNF•Peripheral delivery of FNDC5 via adenoviral vectors induces Bdnf in the hippocampus
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PGC1α is a key transcriptional coregulator of oxidative metabolism and thermogenesis. Through a high-throughput chemical screen, we found that molecules antagonizing the TRPVs (transient receptor ...potential vanilloid), a family of ion channels, induced PGC1α expression in adipocytes. In particular, TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. This role of TRPV4 as a cell-autonomous mediator for both the thermogenic and proinflammatory programs in adipocytes could offer a target for treating obesity and related metabolic diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Significance A unique population of Foxp3 ⁺CD4 ⁺ regulatory T (T ᵣₑg) cells resides in visceral adipose tissue of lean mice. VAT T ᵣₑgₛ are important regulators of local and systemic inflammation and ...metabolism. Here, we show that the VAT T ᵣₑg signature is imposed early in life, well before the typical age-dependent expansion of the adipose-tissue T ᵣₑg population. VAT T ᵣₑgₛ in obese mice lose the signature typical of lean individuals but gain an additional set of over- and underrepresented transcripts. In striking parallel to a pathway recently elucidated in adipocytes, the obese mouse VAT T ᵣₑg signature depends on phosphorylation of a specific residue of PPARγ. These findings are important to consider in designing drugs to target type 2 diabetes and other features of the “metabolic syndrome.”
A unique population of Foxp3 ⁺CD4 ⁺ regulatory T (T ᵣₑg) cells resides in visceral adipose tissue (VAT) of lean mice, especially in the epididymal fat depot. VAT T ᵣₑgₛ are unusual in their very high representation within the CD4 ⁺ T-cell compartment, their transcriptome, and their repertoire of antigen-specific T-cell receptors. They are important regulators of local and systemic inflammation and metabolism. The overall goal of this study was to learn how the VAT T ᵣₑg transcriptome adapts to different stimuli; in particular, its response to aging in lean mice, to metabolic perturbations associated with obesity, and to certain signaling events routed through PPARγ, the “master-regulator” of adipocyte differentiation. We show that the VAT T ᵣₑg signature is imposed early in life, well before age-dependent expansion of the adipose-tissue T ᵣₑg population. VAT T ᵣₑgₛ in obese mice lose the signature typical of lean individuals but gain an additional set of over- and underrepresented transcripts. This obese mouse VAT T ᵣₑg signature depends on phosphorylation of the serine residue at position 273 of PPARγ, in striking parallel to a pathway recently elucidated in adipocytes. These findings are important to consider in designing drugs to target type 2 diabetes and other features of the “metabolic syndrome.”
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
A clear relationship exists between visceral obesity and type 2 diabetes, whereas subcutaneous obesity is comparatively benign. Here, we show that adipocyte-specific deletion of the coregulatory ...protein PRDM16 caused minimal effects on classical brown fat but markedly inhibited beige adipocyte function in subcutaneous fat following cold exposure or β3-agonist treatment. These animals developed obesity on a high-fat diet, with severe insulin resistance and hepatic steatosis. They also showed altered fat distribution with markedly increased subcutaneous adiposity. Subcutaneous adipose tissue in mutant mice acquired many key properties of visceral fat, including decreased thermogenic and increased inflammatory gene expression and increased macrophage accumulation. Transplantation of subcutaneous fat into mice with diet-induced obesity showed a loss of metabolic benefit when tissues were derived from PRDM16 mutant animals. These findings indicate that PRDM16 and beige adipocytes are required for the “browning” of white fat and the healthful effects of subcutaneous adipose tissue.
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•Adipocyte-specific deletion of PRDM16 inhibits beige adipocyte function•Mutant animals develop dietary obesity, insulin resistance, and hepatic steatosis•Mutant subcutaneous fat acquires cellular and molecular properties of visceral fat•PRDM16 may determine key differences between subcutaneous and visceral fat
Loss of PRDM16 inhibits beige adipocyte function and leads to the visceralization of fat.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In ...addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms. Here we record AAC currents directly from inner mitochondrial membranes from various mouse tissues and identify two distinct transport modes: ADP/ATP exchange and H
transport. The AAC-mediated H
current requires free fatty acids and resembles the H
leak via the thermogenic uncoupling protein 1 found in brown fat. The ADP/ATP exchange via AAC negatively regulates the H
leak, but does not completely inhibit it. This suggests that the H
leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP/ATP exchange. By mediating two distinct transport modes, ADP/ATP exchange and H
leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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