Paper of the Week February 25th 2016

How much weight does a person need to lose to improve health? If you relied solely on the news media to determine the impact of excess weight on a persons health, you would (wrongly) assume that overweight individuals all live with type 2 diabetes, high blood pressure and are heart attacks waiting to happen. If they were children or adolescents you would (again wrongly) assume that they have organs that are 10 yrs older than their birthdays and suffer from diseases that they share with their parents. However, the science of overweight tells a much different story. In fact, 50% of adults and youth who are overweight live without any of the chronic diseases that most people associate with obesity. Furthermore, the association between body weight and life expectancy is not a linear relationship. In fact, advocates for being healthy at any size often point to the observation that being overweight may be associated with a lower risk of mortality, when they lobby against the movement for obesity being considered a medical disease.

The intimate link that we often make between obesity and chronic diseases has several consequences, particularly for fellow citizens who are overweight. First, health care providers often focus on excess weight and weight loss as a primary target to achieve “health” for persons who are overweight. Second, for persons living with overweight/obesity focusing on health consequences of overweight creates the unrealistic expectation that they need to achieve a "normal" weight status to avoid chronic diseases. A paper published in Cell Metabolism last week could shift this bias.

For the past 2 decades clinical trials have focused on the best way to lose weight. By and large these studies reveal that a balanced lifestyle change that includes more physical activity, diet modification and frequent contact with a health care professional will lead to a 5-7% weight loss, that in some cases can be sustained for 12-24 months. Believe it or not, we have not identified the magic dietary pattern to achieve these results, nor have we found that HIITing it hard, pumping iron, or becoming marathon runners is any better than getting out and walking more each day. The problem with these studies however, is they focus largely on weight loss and rarely the chronic disease risk factors that accompany excess weight. Importantly, they have failed to identify the impact of modest weight loss on health outcomes. This week's "paper of the week" was designed to address this gap in the literature.

What was the research question? The article of the week, published in Cell Metabolism by Dr. Sam Klein and his team at Washington University, asked the following questions: “What are the metabolic benefits that accompany a simple 5% weight loss”, “Are the benefits related to changes in fat cell (adipocyte) function and “Are these benefits greater if weight loss extends to 10 or 15% of body weight”. Some of this work was discussed in the HBO documentary "Weight of a Nation" in the middle of the trial. These are the first results from this landmark trial.

How did they test the research question? The research team recruited 40 adults who wanted to lose some weight and randomized them to either weight maintenance or weight loss (only 33 completed the entire trial). Weight loss was achieved through weekly behavioural support from an expert, a structured meal plan that targeted reduced fat intake, meal supplements and additional support from a dietitian if they were not meeting targets. The participants in the intervention group were studied after achieving 5% weight loss (~6kg after 3.5 months), 11% weight loss (~11kg after 7 months) and 16% weight loss (~16kg after 11 months). Participants in the control group, were encouraged to maintain they pre-study body weight over the year of the trial.

What did they measure? This was a relatively small study sample because the research team relied on very precise, sophisticated measures of cardiometabolic health. They infused insulin into participants to assess their risk for type 2 diabetes. Participants wore monitors to track their blood pressure over 24 hours. They used MRI techniques to quantify abdominal fat mass and fat in the liver. Finally, they obtained biopsies of fat cells to study how they function and the substances they released. This last measure is important as we know very little about how fat cells adapt to weight loss. For decades we thought fat cells existed only to store energy to be used when food was less abundant. In the late 1990’s a group from Harvard discovered a hormone called leptin that was released from fat cells and seemed to control our appetite. Since then, thousands of studies have documented hundreds of substances, termed adipokines, that are released by fat cells and act on the various tissues in the body. More recently, it’s become clear that fat cells can become dysfunctional as people become obese, releasing cytokines that adversely affect health. What was unclear before this study, was whether this dysfunction was reversible with weight loss and if so, how much weight was needed to rescue the cells.

What did they find?  The intervention group was successful at meeting weight loss targets within the 12 mont trial. Impressively, a small 12 lb weight loss (5% of original body weight) in middle aged persons weighing over 200lbs resulted in improvements of 10-30% in multiple measures of cardiometabolic health. These included reduced blood pressure, liver fat and cholesterol as well as substantial improvements in insulin sensitivity, beta cell function and adipocyte-regulation of fatty acids in the blood. In some cases, the improvements were not greater with increasing weight loss (insulin sensitivity for example), while others particularly beta-cell function, continued to improve when weight loss continued beyond 30 lbs. In an effort to dissect the biological pathways involved in these benefits, the researchers examined the expression of genes involved in the metabolism of the fat cell. While fat cell metabolism was unchanged after 5% weight loss, the expression genes involved in fat storage and inflammation began to shift towards a healthier profile when weight loss improved to 10 and 16% of original body weight (See Figure 2).

Why is this important?  For patients and providers, the key message from this study, is that substantial health benefits are observed with small reductions in body weight. These data should reset patient and provider goals for weight loss and not target a normalization of BMI or body weight. Particularly, when we know that overweight individuals with a low cardiometabolic risk profile live substantially longer than peers with risk factors. Additionally, these data support the concept that the adipocyte is a dynamic organ with functional outcomes that are regulated by weight status. Importantly, the changes in adipocyte dysfunction were reversible with weight loss, but required ~10% weight loss to achieve detectable improvements. The take home message for patients and health care providers: small changes in weight = significant health benefits. Start with small realistic goals and applaud people that achieve them.

Strengths and Limitations: The study relied on precise and accurate tools to assess cardiometabolic risk, but was limited in sample size. Additionally, a substantial number of the control participants dropped out after being randomized to the control group, increasing the risk of a biased sample. Finally, the group specifically avoided the use of activity/exercise in the intervention to avoid the confounding effects of exercise on these cardiometabolic health outcomes. Future studies should determine if these improvements in cardiometabolic health are greater when weight loss is accompanied by regular exercise training or daily physical activity.