Researchers identify key enzyme that controls conversion of white fat to brown fat

hasImmunoblot of Flag-tagged protein PRDM16 in HEK293T cells co-expressing Myc-tagged cullin proteins or an empty vector (Vec). b, Immunoblotting of Endogenous PRDM16 Protein in Inguinal Adipocytes Overexpressing (OE) Flag-tagged CUL2 or Vec. β-actin was used as a loading control. vsChanges in the endogenous stability of PRDM16 in inguinal adipocytes expressing a scrambled control shRNA (control) or targeting shRNAs Ass2 (1 and 2). not = 3 per group. CHX, cycloheximide. RNA-seq transcriptome heat map in differentiated inguinal adipocytes expressing scrambled control (control) or targeting shRNA Ass2 in the presence or absence of forskolin (+cAMP). not = 3 per group. All genes listed are significantly different (false discovery rate (FDR) e, OCR in differentiated inguinal adipocytes expressing scrambled control shRNA or shCul2. OCR values ​​were normalized by total protein (μg). not = 7 (control) and not = 6 (reversal Ass2). AA, antimycin A; Nor., norepinephrine. fOCR in inguinal adipocytes expressing an empty vector or Ass2 normalized by total protein (μg). not = 9 for both groups. gOCR in inguinal adipocytes expressing scrambled control shRNA or shCul2 from WT mice and Prdm16-KO. not = 8 (control × WT), not = 7 (shCul2 × WT), not = 9 (control × Prdm16 KO) and not = 9 (shCul2 × Prdm16 KO). For has and b, representative results are shown from two independent experiments. For bg, the data come from biologically independent samples. For vs and egdata are mean ± sem Values P two-sided were calculated using analysis of variance (ANOVA) (vs) or two-way repeated measures ANOVA (e and f) followed by Tukey’s test (g). *P P P Nature (2022). DOI: 10.1038/s41586-022-05067-4″ width=”800″ height=”530″/>

CUL2 controls PRDM16 protein stability and beige fat biogenesis. aImmunoblotting of Flag-tagged PRDM16 protein into HEK293T cells co-expressing Myc-tagged cullin proteins or an empty vector (Vec). b, Immunoblotting of Endogenous PRDM16 Protein in Inguinal Adipocytes Overexpressing (OE) Flag-tagged CUL2 or Vec. β-actin was used as a loading control. vsChanges in Endogenous PRDM16 Stability in Inguinal Adipocytes Expressing Scrambled Control (Control) or Targeting shRNAs Ass2 (1 and 2). not = 3 per group. CHX, cycloheximide. DRNA-seq transcriptome heat map in differentiated inguinal adipocytes expressing scrambled control (control) or shRNA targeting Ass2 in the presence or absence of forskolin (+cAMP). not = 3 per group. All genes listed are significantly different (false discovery rate (FDR) e, OCR in differentiated inguinal adipocytes expressing scrambled control shRNA or shCul2. OCR values ​​were normalized by total protein (μg). not= 7 (control) and not = 6 (Ass2 tear down). AA, antimycin A; Nor., norepinephrine. FOCR in inguinal adipocytes expressing an empty vector or Ass2 normalized by total protein (μg). not= 9 for both groups. gOCR in inguinal adipocytes expressing scrambled control shRNA or shCul2 from WT and Prdm16- KO mouse. not= 8 (control × WT), not= 7 (shCul2 × WT), not= 9 (control × Prdm16KO) and not= 9 (shCul2 × Prdm16KO). For a and b, representative results are shown from two independent experiments. For bg, the data come from biologically independent samples. For vs and egdata are mean ± sem Pvalues ​​were calculated using a two-way analysis of variance (ANOVA) (vs) or two-way repeated measures ANOVA (e and F) followed by Tukey’s test (g). *PPP Nature (2022). DOI: 10.1038/s41586-022-05067-4

Once thought of as inert tissue, fat – or adipose tissue – is now known to play an active role in critical body functions by secreting hormones that regulate hunger and body temperature. Body fat comes in many varieties; for example, white adipose tissue stores excess energy and brown adipose tissue primarily burns energy. Over the past decade, researchers have isolated a new type of fatty tissue called beige adipose tissue. Beige fat cells begin life as white fat cells, but take on the characteristics of energy-burning brown fat cells under certain circumstances.

A growing body of evidence suggests that brown and beige adipose tissue protects against metabolic diseases, such as insulin resistance and diabetes. Increased production, or biogenesis, of energy-burning beige fat has been associated with substantially improved metabolic health. Now, researchers at Beth Israel Deaconess Medical Center (BIDMC) have developed a transformative approach to making more of this cell type. They identified a key enzyme, Cul2-APPBP2, which catalyzes the degradation of the PRDM16 protein, a potent activator of beige fat biogenesis. The book is available online in the journal Nature.

“The best-known approach to inducing beige fat biogenesis is chronic cold acclimation; however, chronic cold acclimation can be dangerous due to elevated blood pressure, in addition to the fact that exposure to cold is uncomfortable for most people,” said corresponding author Shingo Kajimura, Ph.D., a Howard Hughes Medical Institute researcher in the BIDMC’s Division of Endocrinology, Diabetes and Metabolism. “This work brings a completely new solution by proposing a control model of the biogenesis of beige adipocytes.”

Based on previous work suggesting that the PRDM16 protein plays a key role in beige fat biogenesis, the researchers conducted a series of experiments to determine how protein turnover was controlled in white fat cells in mice. A decade-long discovery, Kajimura and his colleagues have identified the key enzyme – an E3 ligase complex named CUL2-APPBP2 – that breaks down protein in fat cells.

In the absence of the E3 ligase complex, the PRDM16 protein activated heat-producing genes characteristic of beige fat, counteracting diet-induced obesity, glucose intolerance, insulin intolerance and abnormal blood fat levels in mice. Scientists also observed that the protein suppresses damaging pro-inflammatory genes in fat cells, suggesting another pathway by which brown and beige fats contribute to metabolic health.

“We hope that an inhibitor will be an effective approach to stimulate beige fat biogenesis and improve metabolic health safely,” said first author Qiang Wang, an instructor in Kajimura’s lab. “We are now looking for specific inhibitors to block the E3 ligase complex.”


Exposure to cold, capsinoids promote the biogenesis of beige adipocytes


More information:
Shingo Kajimura, Post-translational control of beige fat biogenesis by PRDM16 stabilization, Nature(2022). DOI: 10.1038/s41586-022-05067-4. www.nature.com/articles/s41586-022-05067-4

Provided by Beth Israel Deaconess Medical Center


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