Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals

Bal, Naresh C.; Maurya, Santosh K.; Sopariwala, Danesh H.; Sahoo, Sanjaya Kumar; Gupta, Subash C.; Shaikh, Sana; Pant, Meghna; Rowland, Leslie A.; Bombardier, Éric; Goonasekera, Sanjeewa A.; Tupling, A. Russell; Molkentin, Jeffery D.; Periasamy, Muthu

doi:10.1038/nm.2897

Cited by 455 publications

(582 citation statements)

References 38 publications

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“…S6B). We also did not observe an increase in expression of the gene encoding sarcolipin, a protein implicated in nonshivering thermogenesis in skeletal muscle (21), in soleus muscle of Ad-GsKO mice. Rather, its expression was decreased (Fig.…”

Section: Both Adipose Tissue Lipolysis and Lipogenesis Are Reduced Incontrasting

confidence: 65%

G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

Shrestha

Chen

et al. 2015

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

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G s α, the G protein that transduces receptor-stimulated cAMP generation, mediates sympathetic nervous system stimulation of brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), which are both potential targets for treating obesity, as well as lipolysis. We generated a mouse line with G s α deficiency in mature BAT and WAT adipocytes (Ad-GsKO). Ad-GsKO mice had impaired BAT function, absent browning of WAT, and reduced lipolysis, and were therefore cold-intolerant. Despite the presence of these abnormalities, Ad-GsKO mice maintained normal energy balance on both standard and high-fat diets, associated with decreases in both lipolysis and lipid synthesis. In addition, Ad-GsKO mice maintained at thermoneutrality on a standard diet also had normal energy balance. Ad-GsKO mice had improved insulin sensitivity and glucose metabolism, possibly secondary to the effects of reduced lipolysis and lower circulating fatty acid binding protein 4 levels. G s α signaling in adipose tissues may therefore affect whole-body glucose metabolism in the absence of an effect on body weight. T he sympathetic nervous system (SNS) regulates energy homeostasis and adiposity through several mechanisms, including activation of nonshivering thermogenesis in brown adipose tissue (BAT), browning (formation of BAT-like "beige" cells) of white adipose tissue (WAT), and stimulation of lipolysis. Although these processes have been shown to be potential targets in treating obesity and diabetes (1-3), ablation of sympathetic nerves (4-6) or their main effectors (norepinephrine and epinephrine) (7) does not result in obesity or insulin resistance. Although mice lacking β adrenergic receptors (β-less mice) do develop obesity (8), it is likely that this effect is not due only to loss of β-adrenergic signaling in adipose tissue.The main mediator of SNS function in adipose tissues is G s α (9, 10), a ubiquitously expressed G protein α-subunit that in adipose tissue couples adrenergic and other receptors, such as the adenosine A2A receptor (11), to the generation of intracellular cAMP. We have previously generated adipose-specific G s α knockout mice (FGsKO) using fatty acid binding protein 4 (FABP4) (aP2)-cre and showed these mice to have significant early mortality and a severely lean phenotype (12). However, the usefulness of this model to examine the role of G s α in mature adipocytes is limited due to both the lack of specificity of FABP4-cre expression in adipose tissue and the presence of a severe defect in adipogenesis due to expression of FABP4, and therefore loss of G s α, during an early step in adipocyte differentiation.Adiponectin is a mature adipocyte marker expressed late in adipocyte differentiation (13). The more recent availability of adiponectin-cre mouse lines (14, 15) has enabled us to generate adipose-specific G s α knockout mice (Ad-GsKO) in which G s α deletion is restricted to mature adipocytes. Despite having loss of BAT function or browning of WAT, Ad-GsKO mice failed to develop obesity on either ...

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Section: Both Adipose Tissue Lipolysis and Lipogenesis Are Reduced Incontrasting

confidence: 65%

G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

Shrestha

Chen

et al. 2015

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

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“…At room temperature (20-22 °C), mice are cold and must therefore expend extra energy to defend their body temperature. Ucp1-deficient mice, which cannot use BAT, activate alternative thermogenic mechanisms 55,56 . This is thought to conceal the effect of brown fat and Ucp1 on energy balance.…”

Section: Regulation Of Brown and Beige Adipocytes By Prdm16mentioning

confidence: 99%

Brown and beige fat: development, function and therapeutic potential

Harms

Seale

2013

Nat Med

1,888

1,972

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Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.npg

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“…Specifically expressed in brown and beige/bright adipocytes, UCP1 is required to mediate adaptive thermogenesis [3][4][5] . Nevertheless, UCP1-independent processes exist to regulate energy expenditure [6][7][8] .…”

mentioning

confidence: 99%

The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure

Huang

Ruan

et al. 2014

Nat Commun

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Cell growth is tightly coupled with mitochondrial biogenesis in order to maintain energy and organelle homeostasis. Receptor tyrosine kinase Kit and its ligand, stem cell factor (SCF), play a critical role in the growth and survival of multiple cell lineages. Here we report that the expression of SCF and Kit in adipose tissues is responsive to food availability and environmental temperature, and is altered in obese mice and human patients. Mice carrying a lossof-function mutation in Kit develop obesity as a result of decreased energy expenditure. These phenotypes are associated with reduced PGC-1a expression and mitochondrial dysfunction in brown adipose tissue and skeletal muscle. We further demonstrate that SCF/Kit directly promotes Ppargc1a transcription and mitochondrial biogenesis. Blocking Kit signalling in mice decreases PGC-1a expression and thermogenesis, while overexpressing SCF systemically or specifically in brown adipose tissue increases thermogenesis and reduces weight gain. Collectively, these data provide mechanistic insight into the regulation of mitochondrial function by SCF/Kit signalling and lay a foundation for exploring SCF/Kit signalling as a therapeutic target for metabolic diseases.

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Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals

Cited by 455 publications

References 38 publications

G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

Brown and beige fat: development, function and therapeutic potential

The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure

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Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals

Cited by 455 publications

References 38 publications

G s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

G s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

Brown and beige fat: development, function and therapeutic potential

The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure

Contact Info

Product

Resources

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G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

G _s α deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight