Clinicians and investigators have long understood that weight loss improves diabetes risk factors associated with obesity; however, many patients struggle to maintain weight loss over time. Regaining weight can increase the risk of developing type 2 diabetes and cardiovascular disease (CVD), as well as all-cause mortality.

A continual sequence of weight loss and regain is called weight cycling. Heather Caslin, PhD, Assistant Professor at the University of Houston and Laboratory of Integrated Physiology, studied the harmful effects of weight cycling and presented her key findings during Beyond the Scale—Exploring Causes and Consequences of Weight Fluctuation.

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Dr. Caslin stated that approximately one in five men and one in four women may experience weight cycling over their lifetime.

“If weight cycling really is associated with an increased disease risk, then continually recommending weight loss to those unable to maintain it over time may be a public health issue,” Dr. Caslin said.

Dr. Caslin and an investigative team at Vanderbilt University studied the effects of weight cycling in murine models. Their research found that while weight loss did improve systemic metabolism function, it did not restore type 2 immune cells or reverse the induction of type 1 “inflammatory” cells. The researchers also found that CD8 memory T-cell exhaustion and macrophage lipid handling persist despite weight loss.

“Weight loss wasn’t normalizing the adipose tissue landscape,” Dr. Caslin explained. “Adipose immune cells seem to remember the idea of obesity.”

Over the last decade, immunologists have begun to understand that there is memory in the innate immune system. An innate signal induces metabolic activation and epigenetic reprogramming within the innate immune system, Dr. Caslin noted. Consequently, these cells remain primed, leading to enhanced effector function.

This innate memory response is a protective evolutionary response that improves response to pathogens like candida albicans and mycobacterium tuberculosis, among others. However, the innate memory response can also be induced by oxidated low-density lipoproteins (ox-LDL) or hyperglycemia, leading to harmful consequences.

“These inducers of memory would actually be detrimental to chronic diseases like atherosclerosis, neurodegeneration, and diabetes,” Dr. Caslin said.

Investigators theorized that weight loss and cycling initiated innate immune memory in the adipose macrophages. They found that palmitic acid could replicate the innate immune memory in culture, while another study found the same result in mice. Palmitic acid increased maximal metabolic rates and lipopolysaccharide (LPS)-induced cytokine production. The mechanism behind palmitic acid memory is toll-like receptor 4 (TLR4).

Data from Dr. Caslin’s team showed that while weight loss improved glucose tolerance in mice, the adipose macrophages became primed for increased reactivity to subsequent stimulation from LPS cytokines.

“Macrophages from weight loss mice are hyperinflammatory to things like bacterial stimuli and weight regain, and so this heightened inflammation correlates to worsened glucose tolerance and is a potential causal mechanism that we’ll be investigating,” Dr. Caslin said.

This session also featured presentations from Iris Shai, PhD, Ben Gurion University of the Negev, Israel, on signs of antiaging in lifestyle interventions and Marcus DaSilva Goncalves, MD, PhD, NYU Langone, on nutrient uptake and metabolism during weight loss.