Obesity

Posted on Diabetes, Obesity

Discovery could hold the key to alleviating metabolic disease

A newly characterized fat protein could provide the missing link to explain a rare metabolic disease while offering fresh insight into common disorders such as obesity and type 2 diabetes.

Have you ever been a victim of a hate crime because of your autism?

Scientists have long sought to find out how some diseases can have symptoms restricted to just one tissue when they are caused by a single faulty protein found throughout the body.

Familial Partial Lipodystrophy type 2 (FPLD2) is a rare disorder causing diabetes, loss of fat in the arms and legs and over development of muscles, yet the faulty protein, lamin A, is found in all cells.

University of Edinburgh scientists found that mice lacking the protein Tmem120a, which is mostly found in fat cells, have similar symptoms as FPLD2.

Tmem120a belongs to a group of proteins, known as NETs, that help ensure the cell’s genetic material, found inside the cell’s command centre – the nucleus – is correctly organised and read.

They found that Tmem120a plays a key role in normal development of fat tissue and healthy metabolism by promoting expression of fat genes and shutting off muscle genes in fat tissue.

These effects appear to be due to Tmem120a’s ability to release parts of the genome that control fat metabolism away from the edge of the nucleus while recruiting muscle genes to the edge.

When genes are at the edge of the nucleus they tend to be shut off and the scientists found that the mispositioning of genes in the mice lacking Tmem120a also occurred in human patients with FPLD2.

The study authors propose that because Tmem120a is found mostly in fat tissue that it mediates the fat-specificity of the defect caused by the faulty lamin A protein previously linked to FPLD2.

Studies on genetic defects that cause metabolic disease indicate they are complex with many genes implicated; thus, Tmem120a, by affecting positioning of many genes, could similarly be involved.

The findings could have wider implications for other metabolic diseases, such as diabetes, insulin resistance, glucose intolerance, and obesity, as well as muscle disorders and body building.

The symptoms only became apparent in mice that were fed a high calorie diet, consistent with the symptoms with FPLD2 which often appear later in life and require a carefully controlled diet.

This mechanism could explain why some diseases such as diabetes are only revealed when the body is under pressure – such as the high calorie diet fed to the mice lacking the Tmem120a gene.

Functional defects in other NET proteins are linked to many human diseases such as muscular dystrophies, cardiomyopathy, blood and bone disorders, cancers, and premature aging syndromes.

Other complex diseases could have a similar mechanism in which NETs affecting gene positioning cause small changes in expression of multiple genes so that pathways still function but at reduced capacity, thus producing symptoms only under certain circumstances.

Dr Rafal Czapiewski, first author and Postdoctoral Research Associate, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, said:

“The part that is most interesting for me is the discovery of the new mechanism for muscle growth observed in lipodystrophy that opens new potential avenues for increasing muscle mass that is lost for example in astronauts during space travel, in muscular dystrophy or in muscle loss caused by injuries.”

Posted on Diabetes, Obesity

Antidiabetic drug causes double the weight loss of competitor in Type 2 diabetes patients

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Antidiabetic drug causes double the weight loss of competitor in Type 2 diabetes patients
Antidiabetic drug causes double the weight loss of competitor in Type 2 diabetes patients

Patients with Type 2 diabetes who were prescribed SGLT2 inhibitors lost more weight than patients who received GLP-1 receptor agonists, according to a University at Buffalo-led study.

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The research, which sought to evaluate the difference in weight loss caused by the antidiabetic medications — both of which work to control blood sugar levels — found that among 72 patients, people using SGLT2 inhibitors experienced a median weight loss of more than 6 pounds, while those on GLP-1 receptor agonists lost a median of 2.5 pounds.

The findings, published last month in the Journal of the American Pharmacists Association, represent one of the first attempts to compare the two drugs.

“Weight loss is an advantageous quality for diabetic medications as being overweight is a common characteristic of the disease, and can eventually lead to reduced insulin sensitivity,” said lead author Nicole Paolini Albanese, PharmD, clinical associate professor of pharmacy practice in the UB School of Pharmacy and Pharmaceutical Sciences. “With weight loss, it is possible to regain insulin sensitivity, improve glucose control, and reduce heart risk factors and comorbidities.”

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Both SGLT2 inhibitors and GLP-1 receptor agonists are recommended as second-line therapies for Type 2 diabetes after use of metformin, a drug also prescribed to control blood sugar, says Albanese.

The study examined records for patients with Type 2 diabetes who received either SGLT2 inhibitors or GLP-1 receptor agonists, in addition to other diabetes medications, from 2012-17. The researchers measured weight loss after six months of consecutive therapy, and differences in blood pressure, blood sugar levels and kidney function.

Canagliflozin, sold under the brand name Invokana, was the most commonly prescribed SGLT2 inhibitor. Liraglutide, sold under the brand name Victoza, was the most commonly prescribed GLP-1 receptor agonist.

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No significant differences were found in blood pressure, blood sugar levels and kidney function after use of the medications. The data suggest that SGLT2 inhibitors may be more protective against weight gain caused by other antidiabetic drugs than GLP-1 receptor agonists, says Albanese. The results also counter previous research that has found GLP-1 receptor agonists to be the superior antidiabetic drug for weight loss, she says.

Although the weight loss caused by the drugs is small, the findings warrant larger investigations that examine the medications’ effect on weight, she says.

“These medications at doses approved for treating Type 2 diabetes are not intended for weight loss,” says Albanese. “However, this should not discourage the discussion of this potential benefit, as even a small amount of weight loss is a unique advantage of these drugs, especially when compared to potential weight gain caused from other treatment options.”

Posted on Obesity

Semaglutide found to reduce body weight regardless of patient characteristics, but females and those with lower body weight have better results


New research presented at this year’s European Congress on Obesity (held online, 10-13 May) shows that treatment with the drug semaglutide reduces body weight in adults with overweight or obesity, regardless of their baseline characteristics.

However, the study showed that female participants had slightly better results than males and also that participants with the lowest starting body weight responded slightly better than those with higher body weights. The study is by Professor Robert Kushner, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, and colleagues.

Semaglutide is already approved for treatment for type 2 diabetes in multiple countries, and is under development for treatment of obesity. The STEP trials published over the past year have established the efficacy and safety of semaglutide 2.4 mg in treating people with overweight and obesity. In this new analysis of data from the STEP 1 trial (see link below), the researchers investigated weight loss in subgroups of participants based on their baseline characteristics.

In STEP 1, adults without type 2 diabetes with either a body mass index (BMI) of at least 27 kg/m² plus one or more weight-related comorbidities, or a BMI of 30 kg/m² or above, were enrolled. Participants were randomised to a once-weekly injection of semaglutide 2.4 mg or placebo, both plus lifestyle intervention, for 68 weeks.

The authors looked at what proportions of the participants achieved different levels of weight loss with semaglutide from baseline to week 68 (?20%, 15-<20%, 10-<15%, or 5-<10%) when grouped by different baseline characteristics (age, sex, race [White, Asian, Black or African American, or other], body weight, BMI, waist circumference and glycaemic status [normal blood sugar, or pre-diabetes]). Mean percent weight loss with semaglutide from baseline to week 68 was analysed separately by sex (male, female) and baseline body weight (?115 kg, 100-<115 kg, 90-<100 kg, <90 kg) subgroup.

The original study included 1,961 randomised participants (mean age 46 years, body weight 105.3 kg, BMI 37.9 kg/m²; 74.1% female). For categorical weight loss, the observed proportions of participants with ?20%, 15-<20%, 10-<15% and 5-<10% weight loss at week 68 were 34.8%, 19.9%, 20.0% and 17.6% with semaglutide vs 2.0%, 3.0%, 6.8% and 21.2% with placebo, respectively.

The distribution of participants across weight-loss groups did not appear to be affected by any baseline characteristics, except sex and baseline body weight. Mean percent weight loss at week 68 with semaglutide was greater among females (-18.4%) than males (-12.9%), and in participants with lower vs higher baseline body weight (-18.6% for participants with <90 kg body weight at baseline; -13.9% for participants with ?115 kg baseline body weight).

The authors conclude: “We found that weight loss with once-weekly injections of semaglutide 2.4 mg was seen in all subgroups evaluated and was generally not influenced by baseline characteristics. The exceptions were sex and baseline body weight; female sex and a low baseline body weight were associated with a slightly greater response to semaglutide. These data support the use of semaglutide 2.4 mg across a broad population of patients with overweight or obesity.”

Posted on Obesity

Patients who are overweight or obese at risk of more severe COVID-19

Patients who are overweight or obese have more severe COVID-19 and are highly likely to require invasive respiratory support, according to a new international study. CREDIT i yunmai

Patients who are overweight or obese have more severe COVID-19 and are highly likely to require invasive respiratory support, according to a new international study.

The research, led by the Murdoch Children’s Research Institute (MCRI) and The University of Queensland and published in Diabetes Care, found obese or overweight patients are at high risk for having worse COVID-19 outcomes. They are also more likely to require oxygen and invasive mechanical ventilation compared to those with a healthy weight.

MCRI researcher Dr Danielle Longmore said the findings, which highlighted the relationship between obesity and increased COVID-19 disease burden, showed the need to urgently introduce strategies to address the complex socio-economic drivers of obesity, and public policy measures such as restrictions on junk food advertising.

“Although taking steps to address obesity in the short-term is unlikely to have an immediate impact in the COVID-19 pandemic, it will likely reduce the disease burden in future viral pandemics and reduce risks of complications like heart disease and stroke,” she said.

The study looked at hospitalised SARS-CoV-2 patients from 18 hospitals in 11 countries including China, America, Italy, South Africa and The Netherlands.

Among the 7244 patients aged 18 years and over, 34.8 per cent were overweight and 30.8 per cent were obese.

COVID-19 patients with obesity were more likely to require oxygen and had a 73 per cent greater chance of needing invasive mechanical ventilation. Similar but more modest results were seen in overweight patients. No link was found between being overweight or obese and dying in hospital from COVID-19.

Cardiovascular and pre-existing respiratory diseases were associated with increased odds of in-hospital deaths but not a greater risk for needing oxygen and mechanical ventilation. For patients with pre-existing diabetes, there was increased odds of needing invasive respiratory support, but no additionally increase in risk in those with obesity and diabetes.

Men were at an increased risk of severe COVID-19 outcomes and needing invasive mechanical ventilation. In those aged over 65 years, there was an increased chance of requiring oxygen and higher rates of in-hospital deaths.

The University of Queensland’s Dr Kirsty Short, who co-led the research, said almost 40 per cent of the global population was overweight or obese.

“Obesity is associated with numerous poor health outcomes, including increased risk of cardiometabolic and respiratory disease and more severe viral disease including influenza, dengue and SARS-CoV-1,” she said.

Dr Short said while previous reports indicated that obesity was an important risk factor in the severity of COVID-19, almost all this data had been collected from single sites and many regions were not represented. Moreover, there was a limited amount of evidence available about the effects of being overweight or obese on COVID-19 severity.

“Given the large scale of this study we have conclusively shown that being overweight or obese are independent risk factors for worse outcomes in adults hospitalised with COVID-19,” she said.

MCRI Professor David Burgner, who co-led the research, said the data would help inform immunisation prioritisation for higher-risk groups.

“At the moment, the World Health Organization has not had enough high-quality data to include being overweight or obese as a risk factor for severe COVID-19 disease. Our study should help inform decisions about which higher-risk groups should be vaccinated as a priority,” he said.

Posted on Obesity

New approach for the development of a drug treatment for obesity and the resulting diseases

Beige adipocytes within white adipose tissue (beige adipocytes stained with UCP-1 in green. Lipids are stained in red and F-actin outlining cells especially blood vessels in grey, DNA ist blue) CREDIT Ruth Karlina

The protein Asc-1 regulates whether fat-burning beige or fat-storing white adipocytes are formed, which can have an impact on the development of metabolic diseases. This is shown by a current study of the Helmholtz Zentrum München and the German Center for Diabetes Research (DZD). The results open up new approaches to prevent the development of metabolic diseases. The study has now been published in Nature Communications.

Not all fat is the same: there is white, brown and beige adipose tissue *. While white fat cells serve as energy stores, excess energy is burned in brown and beige fat tissue. Too much white fat is considered unhealthy. If the white adipose tissue increases significantly in adults with obesity, metabolic diseases such as diabetes or metabolic syndrome can develop. The situation is different in children: There, the initial formation of white adipose tissue is a prerequisite for a healthy metabolism. But how does adolescent adipose tissue differs from adult white adipose tissue? To answer this question, researchers have investigated the composition of white adipose tissue of young and adult mice using single cell RNA sequencing**.

Asc-1 promotes the formation of white adipocytes

The researchers found that adolescent adipose tissue differs greatly from adult white fat, especially in terms of the properties and composition of fat precursor cells. The researchers discovered a special subgroup of fat precursor cells in adolescent adipose tissue that contain the protein Asc-1, which is otherwise present in mature adipocytes. These precursor cells differentiate predominantly into white adipocytes, and the formation of “healthy” beige adipocytes is actively suppressed. In further cell biological investigations, the team around first author Lisa Suwandhi were able to show that the loss of Asc-1 function promotes the formation of beige adipocytes.

“These insights into the physiological processes of adipose tissue growth enable us to develop new strategies to prevent the harmful metabolic consequences of obesity,” said last author Dr. Siegfried Ussar. The researchers are already pursuing this approach further. They are currently establishing strategies to modulate Asc-1 function in adipose tissue in the living organism and exploring ways to promote healthy adipose tissue expansion. The goal is to help obese patients maintain a healthy metabolism in the future and thus gain time to treat obesity with a holistic approach.