A New Approach to Obesity Treatment: The NOVA LS18 Planar Light Sheet Microscope Facilitates Research Demonstrating That Zinc Ions Enhance Sympathetically Induced Thermogenesis to Ameliorate Obesity.
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Release time：2023-07-20
Summary： On March 6, 2023, the research team led by Professor Lan Bing at Tongji Hospital, affiliated with the School of Medicine of Tongji University, published in Nature Metabolism a study titled “Thermogenic adipocyte-derived Zinc promotes sympathetic innervation in male mice.” The study revealed that primary zinc ions (Zn) are a factor secreted by thermogenic adipocytes that can enhance sympathetic nerve innervation and thermogenesis in mouse adipose tissue. The work elucidated a positive feedback mechanism through which thermogenic adipocytes and sympathetic neurons mutually regulate one another, a mechanism critical for adaptive thermogenesis and offering potential therapeutic targets and new avenues for addressing obesity.
Preface
On March 6, 2023, the research team led by Professor Lan Bing at Tongji Hospital, affiliated with the School of Medicine of Tongji University, published in Nature Metabolism a study titled “Thermogenic adipocyte-derived Zinc promotes sympathetic innervation in male mice.” The study revealed that primary zinc ions (Zn) are a factor secreted by thermogenic adipocytes that can enhance sympathetic nerve innervation and thermogenesis in mouse adipose tissue. The work elucidated a positive feedback mechanism through which thermogenic adipocytes and sympathetic neurons mutually regulate one another, a mechanism critical for adaptive thermogenesis and offering potential therapeutic targets and novel avenues for addressing obesity.
Adaptive thermogenesis is the heat generated by brown adipose tissue (BAT) and beige adipocytes in response to external stimuli such as cold exposure and exercise. Owing to its remarkable capacity for energy expenditure, adaptive thermogenesis has emerged as a promising strategy for combating global obesity and its associated conditions, including type 2 diabetes and insulin resistance. Thermogenic adipose tissues are densely innervated by sympathetic nerves; sympathetic neurotransmission releases catecholamines that stimulate the expression of mitochondrial uncoupling protein 1 (UCP1) and enhance heat production. Meanwhile, both brown and beige adipocytes also modulate their sympathetic innervation through the secretion of paracrine factors.
In this study, the researchers first crossed Diphtheria Toxin Receptor (DTR) mice with UCP1-Cre–expressing mice to generate Ucp1-DTR mice. They then performed tissue clearing on the mice’s adipose tissue and co‑stained it with tyrosine hydroxylase (TH) to label sympathetic nerves, followed by 3D imaging using the OMX LS18 light-sheet microscope. The results showed that under cold‑induced conditions, ablation of UCP1‑positive thermogenic adipocytes in adipose tissue with diphtheria toxin (DT) led to a substantial reduction in sympathetic innervation of the adipose tissue, indicating that thermogenic adipocytes promote the growth of sympathetic nerve axons (Fig. 1b & 1d in the original text). This effect was also observed upon injection of the β3‑adrenergic receptor antagonist L748337 (Extended Fig. 1e & 1g in the original text).
Fig. 1b and 1d: TH-positive sympathetic nerve staining in subcutaneous white adipose tissue (ScWAT) of Ucp1-DTR mice injected with DT or L748337 at 4°C, respectively.
Original text: Extended Fig. 1e & 1g—TH-positive sympathetic nerve staining results in the brown adipose tissue (BAT) of Ucp1-DTR mice injected with DT and L748337, respectively, at 4°C.
Furthermore, when researchers administered zinc intraperitoneally to mice, sympathetic innervation in both subcutaneous white adipose tissue (scWAT) and brown adipose tissue (BAT) increased. Conversely, local injection of the zinc chelator TPEN into scWAT and BAT resulted in a reduction of sympathetic innervation in these tissues (original Fig. 2c & 2e; original Extended Fig. 2b & 2c). Three-dimensional imaging performed with the NOVAI LS18 light-sheet microscope (click here for more details) clearly demonstrated that zinc promotes sympathetic innervation.
Figure 2c and 2e show the results of TH-positive sympathetic nerve staining in subcutaneous white adipose tissue (scWAT) of mice injected with Zn and the Zn chelator TPEN, respectively.
Original text: Results of TH-positive sympathetic nerve staining in the brown adipose tissue (BAT) of mice injected with Zn and the Zn chelator TPEN, respectively, as shown in Extended Fig. 2b and 2c.
Finally, in experiments involving mice fed a standard diet (RD) versus a high-fat diet (HFD), the researchers observed reduced sympathetic innervation and decreased zinc levels in both brown adipose tissue (BAT) and subcutaneous white adipose tissue (scWAT). More importantly, they identified an upregulation of the zinc‑binding protein metallothionein‑2 (MT2) in obesity. This protein, by chelating zinc ions, diminishes zinc release from thermogenic adipocytes, thereby suppressing sympathetic activity and ultimately reducing energy expenditure.
Original Fig. 4a (left) and Extended Fig. 4a (right): TH-positive sympathetic nerve staining in subcutaneous white adipose tissue (scWAT) and brown adipose tissue (BAT) of C57BL/6 mice fed a normal diet (RD) or a high-fat diet (HFD).
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