Dataset Information

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention.

ABSTRACT: Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β ₃-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC9293664 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention.

Zhu Yi Y Li Na N Huang Mingyang M Chen Xi X An Yu A YA Li Jianping J Zhao Shangang S Funcke Jan-Bernd JB Cao Jianhong J He Zhenyan Z Zhu Qingzhang Q Zhang Zhuzhen Z Wang Zhao V ZV Xu Lin L Williams Kevin W KW Li Chien C Grove Kevin K Scherer Philipp E PE

Acta pharmaceutica Sinica. B 20220226 7

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mecha ...[more]

PMID: 35865093

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Project description:Simple Summary Breastfeeding offers many health benefits for both mothers and infants. However, overnutrition and a steady increase in obesity in the U.S. has made it harder for many mothers to produce and express breastmilk. Moreover, the quality of breastmilk from obese mothers is frequently compromised in that it contains fewer nutrients and more inflammatory components. In this study, we used mice to model this phenomenon. We found that short-term high-fat feeding at the start of breeding reduces litter size and pups’ body weight. It also impairs adipocyte remodeling during lactation. Connexin43 is the primary building block for gap junctions in the adipose tissue. It is postulated to play an essential role in adipose tissue remodeling to accommodate mammary gland development and breastmilk production. Using genetically engineered mice without Connexin43 in their adipocytes, we demonstrated that the deletion of adipocyte Connexin43 affects the disappearance of adipocytes during lactation and affects milk composition, which is postulated to impair the pups’ growth. Altogether, this study suggests that increasing or enhancing adipocyte Connexin43 gap junctions may help obese mothers produce better breastmilk to support their neonates. Abstract Breastfeeding offers a broad spectrum of health benefits for infants. However, overnutrition and a steady increase in maternal obesity in the U.S. have made it harder for many mothers to produce and express breastmilk, and the quality of milk from obese mothers is also frequently compromised. Adipocytes, the primary cell type in the non-lactating breast, display a drastic morphological and functional change during lactation in mice. Lipid-filled adipocytes undergo lipolysis, and lipid droplets disappear to provide fatty acids and energy for breastmilk production. Once the animal stops lactation, these lipid-depleted adipocytes return as lipid-laden cells. This dynamic remodeling of the tissue is likely the result of active intercellular communications. Connexin43 (Cx43) is the most abundant connexin in the mammary adipose tissue that makes up the gap junctions for direct intercellular communications. Its expression is increased during lactation and reduced in obese mammary adipose tissue, which is resistant to lactation-induced remodeling. However, whether Cx43 is required for adipocyte remodeling and breastmilk production to support neonates’ growth has not been established. In this study, we used doxycycline-inducible adipocyte-specific Cx43-deleted mice and demonstrated that adipocyte Cx43 played a vital role in determining the carbohydrate levels in breastmilk, which may subsequently affect neonates’ growth.

Dataset Information

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention.

Publications

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention.

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