In a groundbreaking study conducted by scientists from National Taiwan University, a new understanding of how ketone bodies produced during the lactation period can shape long-term metabolic health has emerged. Published in Nature Metabolism, the research led by Dr. Fu-Jung Lin and Dr. Chung-Lin Jiang reveals that early-life ketogenesis plays a crucial role in programming beige adipose tissue formation through epigenetic regulation, offering insights into the impact of early nutrition on adult physiology.
Ketone bodies, such as β-hydroxybutyrate (βHB), are molecules generated by the liver from fatty acids in low glucose conditions, such as fasting or ketogenic diets. Newborn mammals naturally experience a ketogenic state during suckling due to the high-fat content of breast milk. However, the physiological significance of this neonatal ketosis has been largely unknown until now.
Beige adipocytes, a unique type of fat cell found within white adipose tissue, particularly in the inguinal white adipose tissue (iWAT), possess the ability to burn lipids and glucose to generate heat through non-shivering thermogenesis. By undergoing a process called “browning,” iWAT converts energy-storing white fat into thermogenic beige fat during cold exposure or specific metabolic cues. This transformation helps in maintaining energy balance, improving insulin sensitivity, and combatting obesity and metabolic disorders.
The study at National Taiwan University discovered that early-life ketogenesis is crucial for the development of beige adipocytes. Neonatal mice exhibited a transient increase in circulating βHB levels during lactation. Disruption of this endogenous ketogenesis by premature weaning led to impaired beige fat development, reduced thermogenic capacity, and increased susceptibility to diet-induced obesity later in life. Conversely, enhancing ketogenesis during lactation through supplementation with 1,3-butanediol promoted energy expenditure and beige adipocyte accumulation in offspring, highlighting the importance of the neonatal ketogenic state in shaping long-term metabolic health.
Mechanistically, the researchers identified a specific population of CD81⁺ adipose progenitor cells (APCs) highly responsive to βHB through RNA sequencing analyses. Exposure to βHB induced changes in histone acetylation and β-hydroxybutyrylation at key beige fat regulator promoters, activating their expression and priming progenitors towards beige adipogenesis. This study provides direct evidence of ketone bodies acting as epigenetic modulators, linking early nutritional states to adipose tissue transcriptional programming.
The implications of this research are profound for obesity prevention and infant health. The findings suggest that targeted modulation of ketone signaling during critical developmental periods may counteract inherited metabolic risks and offer new opportunities for early prevention of obesity and related diseases. The study also sheds light on the molecular basis of the well-known association between breastfeeding and reduced childhood obesity risk.
In conclusion, the study by Dr. Fu-Jung Lin, Dr. Chung-Lin Jiang, and their team establishes β-hydroxybutyrate as both a metabolic fuel and an epigenetic regulator, revolutionizing our understanding of developmental metabolism and the enduring impact of early nutritional environments. This discovery opens up avenues for novel strategies in combating obesity and metabolic diseases by manipulating ketone signaling during critical developmental windows.
