Introduction

Over the last 40 years, changing lifestyles have driven a global obesity pandemic, significantly impacting human health ¹. Obesity arises when calorie intake surpasses energy expenditure, disrupting the body's delicate energy balance ². This imbalance leads to fat storage in tissues ill-suited to handle excess lipids, such as the liver and muscles, contributing to type 2 diabetes, cardiovascular disease, and certain cancers ³.

Fat is primarily stored in two types of adipose tissue: white (WAT) and brown (BAT)⁴. WAT is specialized for energy storage, while BAT burns fat and glucose to produce heat. Research now reveals that WAT is far more complex than previously thought, playing a critical role in metabolism and cardiovascular health⁵. When WAT expands uncontrollably due to overeating, it becomes dysfunctional, leading to inflammation, poor vascularization, and increased risk of metabolic diseases ^{6 9}.

The insulin and insulin-like growth factor-1 (IGF-1) signaling system, crucial for coordinating growth and metabolism ⁸, also influences WAT behaviour. Our research investigates how endothelial cells—the inner lining of blood vessels—regulate WAT remodeling in obesity through IGF-1 receptors (IGF-1R). By reducing IGF-1R in endothelial cells, we aim to understand its impact on WAT health and systemic metabolism, offering potential new treatments for obesity-related conditions.

Results

Improved Insulin Sensitivity with Endothelial IGF-1R Knockdown

Using genetically engineered mice lacking IGF-1R in their endothelial cells, we examined their response to a high-fat diet (HFD). Despite consuming the same amount of food as control mice, these mice showed improved insulin sensitivity and increased energy expenditure after two weeks on the HFD. Surprisingly, these improvements occurred without significant changes in body weight, suggesting a metabolic advantage. Additionally, these mice had higher levels of adiponectin, a beneficial hormone that improves insulin sensitivity.

Healthier White Adipose Tissue Remodeling

Under normal conditions, WAT expands during calorie surplus by enlarging fat cells (hypertrophy). However, this process often becomes pathological, leading to tissue dysfunction and inflammation. In mice lacking endothelial IGF-1R, WAT exhibited smaller, healthier fat cells, better vascularization, and increased thermogenic (fat-burning) gene expression. These changes indicate a shift toward a more metabolically active and healthy fat tissue.

Surprisingly, these effects were specific to visceral WAT (eWAT), equivalent to abdominal fat in humans, which is strongly linked to metabolic diseases and normally resistant to beneficial remodelling. Other fat depots, such as subcutaneous fat, showed no significant changes.

Paracrine Signals and the Role of Malonate

We discovered that endothelial cells communicate with WAT through paracrine signaling—releasing molecules that influence neighboring cells. Endothelial cells from IGF-1R knockdown mice secreted more malonate, a small molecule that improved metabolic function in fat cells.

When human fat cells were treated with malonate, they exhibited increased expression of thermogenic and vascularization-related genes. This suggests that malonate acts as a natural regulator of fat tissue health.

Take-Home Messages

1. Adipose Tissue Is Dynamic and Crucial to Metabolic Health: Contrary to its reputation as "just fat," WAT is a highly dynamic organ that influences metabolism and overall health. Dysfunctional WAT contributes to obesity-related complications, but targeting its remodeling offers a promising therapeutic avenue.
2. Endothelial Cells Play a Key Role in Fat Health: The endothelium, long considered merely the lining of blood vessels, actively communicates with fat tissue to regulate its behaviour ^8,9. By modifying endothelial IGF-1R, we demonstrated that this communication could be harnessed to promote healthier fat.
3. Malonate as a Natural Adipose Modulator: The discovery of malonate's role as a paracrine signal opens the door to new treatments. Administering malonate or its derivatives may help transform unhealthy WAT into a metabolically beneficial state.
4. Therapeutic Potential in Obesity and Beyond: Our findings highlight the potential of targeting endothelial signaling pathways to treat obesity and its complications. This approach not only improves fat tissue function but also enhances systemic metabolism, paving the way for innovative therapies.

The Bigger Picture

Obesity affects millions worldwide, increasing the burden of chronic diseases. While lifestyle changes remain critical, novel treatments are urgently needed. By exploring the intricate relationship between blood vessels and fat tissue, our research uncovers new ways to tackle obesity from within.

The next steps involve translating these findings into human therapies. Could malonate-based treatments become part of the arsenal against obesity? Ongoing studies will help answer this question, but one thing is clear: understanding the biology of fat holds the key to healthier futures.

References

1. Swinburn, B. A. et al. The global obesity pandemic: shaped by global drivers and local environments. The Lancet 378, 804–814 (2011).
2. Mozaffarian, D., Hao, T., Rimm, E. B., Willett, W. C. & Hu, F. B. Changes in Diet and Lifestyle and Long-Term Weight Gain in Women and Men. New England Journal of Medicine 364, 2392–2404 (2011).
3. Hruby, A. et al. Determinants and Consequences of Obesity. Am J Public Health 106, 1656–1662 (2016).
4. Kajimura, S., Spiegelman, B. M. & Seale, P. Brown and Beige Fat: Physiological Roles beyond Heat Generation. Cell Metab 22, 546–559 (2015).
5. Kershaw, E. E. & Flier, J. S. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89, 2548–2556 (2004).
6. Pellegrinelli, V., Carobbio, S. & Vidal-Puig, A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia 59, 1075–1088 (2016).
7. Haywood, N. J., Slater, T. A., Matthews, C. J. & Wheatcroft, S. B. The insulin like growth factor and binding protein family: Novel therapeutic targets in obesity & diabetes. Mol Metab 19, (2019).
8. Haywood, N. J. & Kearney, M. T. Emerging paracrine functions of the endothelium in the setting of diabetes. Curr Opin Physiol 34, 100668 (2023).
9. Luk, C., Haywood, N. J., Bridge, K. I. & Kearney, M. T. Paracrine Role of the Endothelium in Metabolic Homeostasis in Health and Nutrient Excess. Front Cardiovasc Med 9, (2022).