Metabolic memory: mechanisms and diseases

Abstract

Metabolic diseases and their complications impose health and economic burdens worldwide. Evidence from past experimental studies and clinical trials suggests our body may have the ability to remember the past metabolic environment, such as hyperglycemia or hyperlipidemia, thus leading to chronic inflammatory disorders and other diseases even after the elimination of these metabolic environments. The long-term effects of that aberrant metabolism on the body have been summarized as metabolic memory and are found to assume a crucial role in states of health and disease. Multiple molecular mechanisms collectively participate in metabolic memory management, resulting in different cellular alterations as well as tissue and organ dysfunctions, culminating in disease progression and even affecting offspring. The elucidation and expansion of the concept of metabolic memory provides more comprehensive insight into pathogenic mechanisms underlying metabolic diseases and complications and promises to be a new target in disease detection and management. Here, we retrace the history of relevant research on metabolic memory and summarize its salient characteristics. We provide a detailed discussion of the mechanisms by which metabolic memory may be involved in disease development at molecular, cellular, and organ levels, with emphasis on the impact of epigenetic modulations. Finally, we present some of the pivotal findings arguing in favor of targeting metabolic memory to develop therapeutic strategies for metabolic diseases and provide the latest reflections on the consequences of metabolic memory as well as their implications for human health and diseases.

Fig. 1

The research history of metabolic memory. The term “metabolic memory” originated from the study of the pathogenesis of long-term diabetic complications by the Diabetes Control and Complications Trial (DCCT) in 1983. In 1994, a long-term prospective, longitudinal, observational study conducted by Epidemiology of Diabetes Interventions and Complications (EDIC) found that the risk of complications in diabetic patients with regular glycemic control was higher in the conventional treatment group than in the early intensive control group. This phenomenon has been characterized as “metabolic memory” by the DCCT/EDIC. The following clinical trials, like UKPDS and Steno-2 trials, also revealed early intensive glycemic control might bring about prolonged benefits in diabetes care. Nowadays, the concept of metabolic memory and its implications have been expanded, especially in hyperglycemia, hyperlipidemia, hypoxia, and other metabolic disorders

Fig. 2

The characteristics of metabolic memory. Metabolic memory has three distinct hallmarks. Firstly, the long-term adverse effects on diabetic complications depend on early glycemic control, as subsequent glycemic control does not prevent progression. Secondly, metabolic memory promotes inflammatory changes, premature cell senescence, and ongoing apoptosis, perpetuating the harmful effects even after hyperglycemia is resolved. Thirdly, the establishment of metabolic memory is highly associated with epigenetic modifications, contributing to the enduring adverse effects and progression of diabetic complications. The figure was created with the assistance of Servier Medical Art (https://smart.servier.com/)

Fig. 3

An overview of the interplay between epigenetic modifications and metabolic reprogramming during metabolic memory. The molecular mechanisms of metabolic memory mainly include epigenetic modifications and metabolic reprogramming. Accumulation of metabolic intermediates induces epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). DNA methylation and histone modifications take place at the level of chromatin, while ncRNAs modulate gene expression mainly at post-translational level. Epigenetic modifications could induce persistent expression of metabolic disease-related genes and pro-inflammatory genes, which interact and work together

Fig. 4

Different cell types involved in metabolic memory. Multiple types of cells are involved in the development of metabolic memory-mediated metabolic diseases and their complications. Different cells crosstalk with each other and work together to cause disease progression

Fig. 5

Complex interplay between metabolic memory and metabolic memory-regulated diseases. Metabolic disorders (including hyperglycemia, hyperlipidemia, hyperuricemia, hypoxia, and malnutrition) may induce epigenetic modifications and metabolic reprogramming at molecular and cellular levels, which take a toll on chronic inflammation and oxidative stress. Some metabolic end products, inflammatory cytokines, and reactive oxygen species could affect epigenetic regulations in return. Then, the epigenetic landscape and metabolic reprogramming could destroy the structure and function of different cells and tissues, manifesting as cell proliferation, immunocyte recruitment, cellular apoptosis, fibrosis, and senescence. The long-term accumulation of cellular and tissue dysregulation could give rise to metabolic memory-associated diseases, even after the elimination of metabolic disorders. The figure was created with BioRender.com (https://biorender.com/)