Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Porter, Craig; Annamalai, Palam; Enerbäck, Sven; Lidell, Martin E.; Saraf, Manish Kumar; Labbé, Sébastien M.; Hurren, Nicholas M.; Yfanti, Christina; Chao, Tony; Andersen, Clark R.; Cesani, Fernando; Hawkins, Hal K.; Sidossis, Labros S.

doi:10.2337/db14-0746

Cited by 670 publications

(607 citation statements)

References 37 publications

Supporting

Mentioning

572

Contrasting

Unclassified

Order By: Relevance

“…In conclusion, although the level of functional BAT is inversely correlated with adiposity in humans (36,37) and positively correlated with improved insulin sensitivity and glucose metabolism in mice and humans (38)(39)(40), our results suggest that reduced BAT function alone may be insufficient for the development of obesity or insulin resistance. Moreover, specific inhibition of adipose tissue G s α signaling seems to dramatically affect whole-body glucose metabolism in the absence of an effect on body weight.…”

Section: Discussionmentioning

confidence: 60%

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.

View full text Add to dashboard Cite

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 ...

show abstract

Section: Discussionmentioning

confidence: 60%

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.

View full text Add to dashboard Cite

show abstract

“…Studies have shown that an increased amount of BAT is associated with weight loss in obese subjects, and increased brown fat cell differentiation leads to an increase in energy consumption and reduction in body weight gain and diet-induced obesity (5)(6)(7). BAT also regulates glucose homeostasis and improves insulin sensitivity (8,9), and brown adipogenesis is suppressed in human subjects with insulin resistance (10). Hence, stimulating brown fat formation could be a novel route to fight against obesity and related metabolic disorders (11).…”

mentioning

confidence: 99%

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

Than

Chua

et al. 2015

Journal of Biological Chemistry

104

View full text Add to dashboard Cite

Background:The autocrine regulatory effects of apelin on self-remodeling of adipose tissue are not known. Results: Apelin enhances not only the differentiation and metabolic activity of brown adipocytes but also the browning of white adipocytes. Conclusion: Apelin-APJ signaling promotes adipose tissue browning. Significance: Apelin signaling may serve as a potential therapeutic target for obesity and associated metabolic diseases.

show abstract

“…below thermoneutrality [86] (Figure 5). In humans, acute cold exposure activates BAT especially around the neck and in the supraclavicular area (reviewed in [4]) and increases energy expenditure in proportion to BAT activation [87], [88]. Using PET it has been shown that cold stimulates activation of BAT and increases fatty acid oxidation in this depot, but not in skeletal muscle or subcutaneous adipose tissue [88].…”

Section: Browning Of Wat As a Possible Aid To Fight Metabolic Diseasesmentioning

confidence: 99%

“…The same authors studied the effects of mild cold stimulation (18°C) on dietary fatty acid (DFA) tissue extraction and oxidation in non-cold-acclimated men; after a standard liquid meal containing the long-chain fatty acid PET tracer FTHA, they observed that fractional (not total) DFA extraction in BAT was much greater than in skeletal muscle or white adipose tissue [109]. Chondronikola et al [87] showed that 5-8 h cold exposure increases whole-body energy expenditure, glucose homeostasis, and insulin sensitivity and that prolonged cold exposure stimulates genes associated with lipolysis but only in BAT and not in WAT when compared to thermoneutral conditions [110], although whole body lipolysis, FFA oxidation and TG-FFA cycling were all increased. Taken together these results suggest that BAT, despite its small size, might play a role in whole body lipid metabolism and postprandial lipid handling, if not directly at least indirectly.…”

Section: Activation Of Bat For the Improvement Of Lipid And Glucose Mmentioning

confidence: 99%

The color of fat and its central role in the development and progression of metabolic diseases

Gaggini

Carli

Gastaldelli

2017

Hormone Molecular Biology and Clinical Investigation

View full text Add to dashboard Cite

Abstract:Excess caloric intake does not always translate to an expansion of the subcutaneous adipose tissue (SAT) and increase in fat mass. It is now recognized that adipocyte type (white, WAT, or brown, BAT), size (large vs. small) and metabolism are important factors for the development of cardiometabolic diseases. When the subcutaneous adipose tissue is not able to expand in response to increased energy intake the excess substrate is stored as visceral adipose tissue or as ectopic fat in tissues as muscle, liver and pancreas. Moreover, adipocytes become dysfunctional (adiposopathy, or sick fat), adipokines secretion is increased, fat accumulates in ectopic sites like muscle and liver and alters insulin signaling, increasing the demand for insulin secretion. Thus, there are some subjects that despite having normal weight have the metabolic characteristics of the obese (NWMO), while some obese expand their SAT and remain metabolically healthy (MHO). In this paper we have reviewed the recent findings that relate the metabolism of adipose tissue and its composition to metabolic diseases. In particular, we have discussed the possible role of dysfunctional adipocytes and adipose tissue resistance to the antilipolytic effect of insulin on the development of impaired glucose metabolism. Finally we have reviewed the possible role of BAT vs. WAT in the alteration of lipid and glucose metabolism and the recent studies that have tried to stimulate browning in human adipose tissue.

show abstract

Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Cited by 670 publications

References 37 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

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

The color of fat and its central role in the development and progression of metabolic diseases

Contact Info

Product

Resources

About

Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Cited by 670 publications

References 37 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

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

The color of fat and its central role in the development and progression of metabolic diseases

Contact Info

Product

Resources

About

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