Gene Identified that Regulates Fat Accumulation

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With both a normal diet, and a a high-fat diet, a lack of Panx1 increases cell size. Top rows show lower magnification (scale bar = 0.1 mm) and bottom rows are the insets showing higher magnification of the same image (scale bar = 0.05 mm). [University of Western Ontario]

Scientists at the University of Western Ontario have identified a glycoprotein, Pannexin 1 (Panx1), which plays a key role in regulating the formation of adipocytes and fat accumulation. In vivo studies showed that knockout mice lacking the Panx1 gene from an early developmental stage accumulated a much greater total fat mass compared with wild-type (WT) mice, whether they were fed a normal diet or a high-fat diet. Absence of the Panx1 protein also led to increased insulin and blood glucose levels, which increased the risk of type 2 diabetes.

Reporting in Scientific Reports, the team says the findings point to Panx1 as a key component in the regulation of fat accumulation, and “a potential new target for obesity intervention.”

“What this tells us is that if you have this deletion in mice or loss-of-function mutation in humans that makes Panx1 work improperly, then you might be prone to accumulate more fat,” commented Silvia Penuela, Ph.D., assistant professor at Western’s Schulich School of Medicine & Dentistry, and lead author of the team’s study. “This is the first study to show a link between Panx1 and fat accumulation.” The results are described in a paper titled, “Pannexin 1 regulates adipose stromal cell differentiation and fat accumulation.”

The “obesity epidemic” is a leading cause of death worldwide, with World Health Organization figures suggesting that about 10% of the global population is now obese, the authors write. Obesity also accounts for comorbidities including type 2 diabetes, cancer, and cardiovascular disease. Adipocytes formed from differentiated adipose-derived stromal cells (ASCs) are the main cell type that accumulates fat in the body. These cells have an innate ability to store lipids, which leads to excess adipose tissue formation.

Pannexin proteins (Panx1, Panx2, and Panx3) are a family of glycoproteins that form channels between the cell surface and intracellular compartments, and so are involved in cell signaling. Panx1 has been reported to regulate cell proliferation and differentiation in many different cell types during early development, but its function in early adipogenic development isn’t understood.

The Western Ontario team’s prior work using a Panx1 knockout (KO) mouse model had shown that mice lacking the gene developed increased fat layers from as early as four days after birth, continuing into adulthood. Based on these findings the team hypothesized that Panx1 may regulate adipogenic cell proliferation and differentiation, leading to changes in fat accumulation.

Their latest studies first confirmed that Panx1 KO mice accumulated 42% more fat mass than normal, WT mice. Interestingly, when both groups of mice were fed a high-fat diet (HFD), the Panx1 KO animals accumulated more fat than WT animals but gained weight at the same rate as WT controls. Further investigation showed that the Panx1 KO animals were more active and slept less than the WT controls, which may have explained why they didn’t put on more overall weight. “… the KO mice do not gain more weight under an intense high-fat diet, which may be due to their increased activity and decreased sleep relative to their WT counterparts,” the researchers state.  There was no significant difference in the activity and sleep levels of WT and Panx1 KO animals fed on a normal diet.

Additional studies confirmed that Panx1 is expressed in ASCs in WT animals, and showed that when Panx1 is missing from ASCs their proliferation in culture is compromised, “… with an approximately 50% reduction in total cell number compared to WT ASCs …” the team noted. “… Panx1 KP ASCs proliferate significantly slower than WT ASCs, but there was no effect on cell death.”

Follow-on analyses indicated that Panx1 expression is upregulated in parallel with the induction of adipogenesis in WT ASCs. When WT and Panx1 KO ASCs were grown in culture and induced to undergo adipogenic differentiation, the Panx1 KO cells accumulated more intracellular lipid than the WT ASCs. In vivo studies suggested that lack of Panx1 was associated with increased adipocyte cell area—which indicates hypertrophy, or excessive growth of the individual fat cells—in the subcutaneous fat pads of Panx1 KO mice under both normal and high-fat diet feeding regimes. Adipocyte numbers were lower in the fat pads of Panx1 KO animals fed a normal diet. “Under a high-fat diet, a similar trend was observed for lower numbers of Panx1 KO adipocytes, but it was not statistically significant,” the authors wrote.

They say that their study shows for the first time that “Panx1 regulates the proliferation and differentiation of ASCs into mature adipocytes, and that germline deletion of Panx1 in ASCs leads to increased adipogenic differentiation and fat accumulation.” The use of Panx1 KO mice with germline depletion also allowed the assessment of the gene’s role during the earliest stages of adipogenesis, “where we observed that the lack of Panx1 in progenitor-stem-like cells significantly affected proliferation and differentiation in vitro, and fat accumulation in vivo.”

“When the mice don’t have Panx1, there is more hypertrophy—so their fat cells are much larger and accumulate more fat,” Dr. Penuela noted. “The next step in our research is to look at the levels of expression of Panx1 in human fat cells, and examine the presence of potential mutations in the Panx1 gene in samples taken from patients that suffer from obesity in comparison to donors with a healthy body weight. In the very early days of this research, we are already starting to show a connection.”

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