Inducible Brown Adipose Tissue, or Beige Fat, Is Anabolic for the Skeleton

Abstract It is known that insulin resistance and type 2 diabetes mellitus are associated with increased fractures and that brown adipose tissue (BAT) counteracts many if not all of the symptoms associated with type 2 diabetes. By the use of FoxC2AD+/Tg mice, a well-established model for induction of BAT, or beige fat, we present data extending the beneficial action of beige fat to also include a positive effect on bone. FoxC2AD+/Tg mice are lean and insulin-sensitive and have high bone mass due to increased bone formation associated with high bone turnover. Inducible BAT is linked to activation of endosteal osteoblasts whereas osteocytes have decreased expression of the Sost transcript encoding sclerostin and elevated expression of Rankl. Conditioned media (CM) collected from forkhead box c2 (FOXC2)-induced beige adipocytes activated the osteoblast phenotype and increased levels of phospho-AKT and β-catenin in recipient cells. In osteocytes, the same media decreased Sost expression. Immunodepletion of CM with antibodies against wingless related MMTV integration site 10b (WNT10b) and insulin-like growth factor binding protein 2 (IGFBP2) resulted in the loss of pro-osteoblastic activity, and the loss of increase in the levels of phospho-AKT and β-catenin. Conversely, CM derived from cells overexpressing IGFBP2 or WNT10b restored osteoblastic activity in recipient cells. In conclusion, beige fat secretes endocrine/paracrine activity that is beneficial for the skeleton.

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Brown and Beige Fat: Therapeutic Potential in Obesity

The Indonesian Biomedical Journal ◽

10.18585/inabj.v6i2.32 ◽

2014 ◽

Vol 6 (2) ◽

pp. 65

Author(s):

Anna Meiliana ◽

Andi Wijaya

Keyword(s):

Metabolic Disease ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Therapeutic Effects ◽

Brown Adipocytes ◽

Brown Adipose ◽

Beige Adipocytes ◽

Beige Fat ◽

Adipose Organ

BACKGROUND: The epidemic of obesity and type 2 diabetes presents a serious challenge to scientific and biomedical communities worldwide. There has been an upsurge of interest in the adipocyte coincident with the onset of the obesity epidemic and the realization that adipose tissue plays a major role in the regulation of metabolic function.CONTENT: 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.SUMMARY: The complexity of adipose tissue presents numerous challenges but also several opportunities for therapeutic intervention. There is persuasive evidence from animal models that enhancement of the function of brown adipocytes, beige adipocytes or both in humans could be very effective for treating type 2 diabetes and obesity. Moreover, there are now an extensive variety of factors and pathways that could potentially be targeted for therapeutic effects. In particular, the discoveries of circulating factors, such as irisin, fibroblast growth factor (FGF)21 and natriuretic peptides, that enhance brown and beige fat function in mice have garnered tremendous interest. Certainly, the next decade will see massive efforts to use beige and brown fat to ameliorate human metabolic disease.KEYWORDS: obesity, white adipose tissue, brown adipose tissue, beige adipose tissue, adipose organ, thermogenesis, energy expenditure

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Anatomical Locations of Human Brown Adipose Tissue: Functional Relevance and Implications in Obesity and Type 2 Diabetes

Diabetes ◽

10.2337/db12-1430 ◽

2013 ◽

Vol 62 (6) ◽

pp. 1783-1790 ◽

Cited By ~ 138

Author(s):

H. Sacks ◽

M. E. Symonds

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Brown Adipose ◽

Functional Relevance

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Melatonin Enhances the Mitochondrial Functionality of Brown Adipose Tissue in Obese—Diabetic Rats

Antioxidants ◽

10.3390/antiox10091482 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1482

Author(s):

Ahmad Agil ◽

Miguel Navarro-Alarcon ◽

Fatma Abo Zakaib Ali ◽

Ashraf Albrakati ◽

Diego Salagre ◽

...

Keyword(s):

Type 2 Diabetes ◽

Superoxide Dismutase ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Brown Fat ◽

Superoxide Dismutase Activity ◽

Atp Production ◽

Brown Adipose ◽

Zdf Rats

Developing novel drugs/targets remains a major effort toward controlling obesity-related type 2 diabetes (diabesity). Melatonin controls obesity and improves glucose homeostasis in rodents, mainly via the thermogenic effects of increasing the amount of brown adipose tissue (BAT) and increases in mitochondrial mass, amount of UCP1 protein, and thermogenic capacity. Importantly, mitochondria are widely known as a therapeutic target of melatonin; however, direct evidence of melatonin on the function of mitochondria from BAT and the mechanistic pathways underlying these effects remains lacking. This study investigated the effects of melatonin on mitochondrial functions in BAT of Zücker diabetic fatty (ZDF) rats, which are considered a model of obesity-related type 2 diabetes mellitus (T2DM). At five weeks of age, Zücker lean (ZL) and ZDF rats were subdivided into two groups, consisting of control and treated with oral melatonin for six weeks. Mitochondria were isolated from BAT of animals from both groups, using subcellular fractionation techniques, followed by measurement of several mitochondrial parameters, including respiratory control ratio (RCR), phosphorylation coefficient (ADP/O ratio), ATP production, level of mitochondrial nitrites, superoxide dismutase activity, and alteration in the mitochondrial permeability transition pore (mPTP). Interestingly, melatonin increased RCR in mitochondria from brown fat of both ZL and ZDF rats through the reduction of the proton leak component of respiration (state 4). In addition, melatonin improved the ADP/O ratio in obese rats and augmented ATP production in lean rats. Further, melatonin reduced mitochondrial nitrosative and oxidative status by decreasing nitrite levels and increasing superoxide dismutase activity in both groups, as well as inhibited mPTP in mitochondria isolated from brown fat. Taken together, the present data revealed that chronic oral administration of melatonin improved mitochondrial respiration in brown adipocytes, while decreasing oxidative and nitrosative stress and susceptibility of adipocytes to apoptosis in ZDF rats, suggesting a beneficial use in the treatment of diabesity. Further research regarding the molecular mechanisms underlying the effects of melatonin on diabesity is warranted.

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Brown adipose tissue, thermogenesis, angiogenesis: pathophysiological aspects

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2014-0014 ◽

2014 ◽

Vol 19 (1) ◽

Cited By ~ 3

Author(s):

Jennifer Honek ◽

Sharon Lim ◽

Carina Fischer ◽

Hideki Iwamoto ◽

Takahiro Seki ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Causes Of Death ◽

Brown Adipose ◽

Common Causes ◽

Brown Adipose Tissue Thermogenesis ◽

Thermogenic Capacity

AbstractThe number of obese and overweight individuals is globally rising, and obesity-associated disorders such as type 2 diabetes, cardiovascular disease and certain types of cancer are among the most common causes of death. While white adipose tissue is the key player in the storage of energy, active brown adipose tissue expends energy due to its thermogenic capacity. Expanding and activating brown adipose tissue using pharmacological approaches therefore might offer an attractive possibility for therapeutic intervention to counteract obesity and its consequences for metabolic health.

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The Relationship Between Brown Adipose Tissue Content in Supraclavicular Fat Depots and Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus and Prediabetes

Diabetes Technology & Therapeutics ◽

10.1089/dia.2016.0360 ◽

2017 ◽

Vol 19 (2) ◽

pp. 96-102 ◽

Cited By ~ 15

Author(s):

Ekaterina Koksharova ◽

Dmitry Ustyuzhanin ◽

Yury Philippov ◽

Alexander Mayorov ◽

Marina Shestakova ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Brown Adipose Tissue ◽

Fat Depots ◽

Brown Adipose ◽

The Relationship

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Cold and Exercise: Therapeutic Tools to Activate Brown Adipose Tissue and Combat Obesity

Biology ◽

10.3390/biology8010009 ◽

2019 ◽

Vol 8 (1) ◽

pp. 9 ◽

Cited By ~ 8

Author(s):

Carmem Peres Valgas da Silva ◽

Diego Hernández-Saavedra ◽

Joseph White ◽

Kristin Stanford

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Lipid Uptake ◽

Mitochondrial Uncoupling ◽

Bat Activity ◽

Brown Adipose

The rise in obesity over the last several decades has reached pandemic proportions. Brown adipose tissue (BAT) is a thermogenic organ that is involved in energy expenditure and represents an attractive target to combat both obesity and type 2 diabetes. Cold exposure and exercise training are two stimuli that have been investigated with respect to BAT activation, metabolism, and the contribution of BAT to metabolic health. These two stimuli are of great interest because they have both disparate and converging effects on BAT activation and metabolism. Cold exposure is an effective mechanism to stimulate BAT activity and increase glucose and lipid uptake through mitochondrial uncoupling, resulting in metabolic benefits including elevated energy expenditure and increased insulin sensitivity. Exercise is a therapeutic tool that has marked benefits on systemic metabolism and affects several tissues, including BAT. Compared to cold exposure, studies focused on BAT metabolism and exercise display conflicting results; the majority of studies in rodents and humans demonstrate a reduction in BAT activity and reduced glucose and lipid uptake and storage. In addition to investigations of energy uptake and utilization, recent studies have focused on the effects of cold exposure and exercise on the structural lipids in BAT and secreted factors released from BAT, termed batokines. Cold exposure and exercise induce opposite responses in terms of structural lipids, but an important overlap exists between the effects of cold and exercise on batokines. In this review, we will discuss the similarities and differences of cold exposure and exercise in relation to their effects on BAT activity and metabolism and its relevance for the prevention of obesity and the development of type 2 diabetes.

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