Directing visceral white adipocyte precursors to a thermogenic adipocyte fate improves insulin sensitivity in obese mice

Hepler, Chelsea; Shao, Mengle; Xia, Jonathan Y.; Ghaben, Alexandra L.; Pearson, Mackenzie; Vishvanath, Lavanya; Sharma, Ankit X.; Morley, Thomas S.; Holland, William L.; Gupta, Rana K.

doi:10.7554/elife.27669

Cited by 39 publications

(37 citation statements)

References 55 publications

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“…An increasing number of studies support that activation of the thermogenic program in the adipose tissue beneficially impacts on glucose and lipid homeostasis and insulin sensitivity, especially in the context of energy overload and obesity [9,10,22,23]. In the HFD-fed foz/foz mouse model we used, low-thermogenic BAT function accompanies severe insulin resistance and morbid obesity [11].…”

Section: Discussionmentioning

confidence: 99%

Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis

Poekes

Gillard

Farrell

et al. 2019

Laboratory Investigation

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Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.

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Section: Discussionmentioning

confidence: 99%

Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis

Poekes

Gillard

Farrell

et al. 2019

Laboratory Investigation

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“…In contrast to the protective role of SAT, excess VAT is indeed associated with a cluster of metabolic abnormalities referred to as metabolic syndrome. Research about VAT has been getting more and more attention . According to the first reports of Oberkofler et al, reduced UCP1 mRNA levels in VAT of humans with obesity had been observed .…”

Section: Discussionmentioning

confidence: 99%

MiR‐27b‐3p Regulation in Browning of Human Visceral Adipose Related to Central Obesity

et al. 2017

Obesity

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“…Our own work on the transcription factor ZFP423 also sheds insight into plasticity of mature adipocytes (22,33). Zfp423 expression is enriched in white versus brown adipocytes and is suppressed in fat cells upon cold exposure or direct activation of b3-adrenergic signaling (22).…”

Section: Beige Cells Can Arise From Differentiated Unilocular Adipocytesmentioning

confidence: 99%

Cellular Origins of Beige Fat Cells Revisited

et al. 2019

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Activated beige adipocytes have therapeutic potential due to their ability to improve glucose and lipid homeostasis. To date, the origin of beige adipocytes remains enigmatic. Whether beige cells arise through de novo differentiation from resident precursors or through reprogramming of mature white adipocytes has been a topic of intense discussion. Here, we offer our perspective on the natural origin of beige adipocytes in mice. In particular, we revisit recent lineage-tracing studies that shed light on this issue and offer new insight into how environmental housing temperatures early in life influence the mode of beige adipocyte biogenesis upon cold exposure later in life. We suggest a unified model in which beige adipocytes (UCP1 + multilocular cells) in rodents initially arise predominantly from progenitors (i.e., de novo beige adipogenesis) upon the first exposure to cold temperatures and then interconvert between "dormant beige" and "active beige" phenotypes (i.e., beige cell activation) upon subsequent changes in environmental temperature. Importantly, we highlight experimental considerations needed to visualize de novo adipogenesis versus beige cell activation in mice. A precise understanding of the cellular origins of beige adipocytes emanating in response to physiological and pharmacological stimuli may better inform therapeutic strategies to recruit beige adipocytes in vivo.

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Directing visceral white adipocyte precursors to a thermogenic adipocyte fate improves insulin sensitivity in obese mice

Cited by 39 publications

References 55 publications

Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis

Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis

MiR‐27b‐3p Regulation in Browning of Human Visceral Adipose Related to Central Obesity

Cellular Origins of Beige Fat Cells Revisited

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