OBJECTIVE: Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS: We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS: We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell–like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS: Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

The first 1,000 days in the life of a human being are a vulnerable stage where early stimuli may program adverse health outcomes in future life. Proper maternal nutrition before and during pregnancy modulates the development of the fetus, a physiological process known as fetal programming. Defective programming promotes non-communicable chronic diseases in the newborn which might be prevented by postnatal interventions such as breastfeeding. Breast milk provides distinct bioactive molecules that contribute to immune maturation, organ development, and healthy microbial gut colonization, and also secures a proper immunological response that protects against infection and inflammation in the newborn. The gut microbiome provides the most critical immune microbial stimulation in the newborn in early life, allowing a well-trained immune system and efficient metabolic settings in healthy subjects. Conversely, negative fetal programming by exposing mothers to diets rich in fat and sugar has profound effects on breast milk composition and alters the immune profiles in the newborn. At this new stage, newborns become vulnerable to immune compromise, favoring susceptibility to defective microbial gut colonization and immune response. This review will focus on the importance of breastfeeding and its immunological biocomponents that allow physiological immune programming in the newborn. We will highlight the importance of immunological settings by breastfeeding, allowing proper microbial gut colonization in the newborn as a window of opportunity to secure effective immunological response.