Study of the Hypothalamic Microglial Response as a Function of a Meal's Lipid Content in Humans. A Single-center Prospective Cohort Study in Healthy Male Subjects

Overview

Obesity and its complications represent a growing public health problem in our society. A better understanding of the biological mechanisms involved in regulating food intake-and, more broadly, energy metabolism-should lead to improved management of this condition. Recent studies have shown that eating a single meal can rapidly trigger the activation of the immune system. This leads to a postprandial, systemic, and transient inflammatory response (Emerson SR, Adv Nutr 2017). It is found in both healthy and obese individuals. It has also been observed in rodents, enabling preclinical studies to better understand the phenomenon. This postprandial inflammation is characterized by the activation of macrophages in the gastrointestinal tract and by elevated levels of circulating pro-inflammatory markers. At the cellular level, nutrients activate an intracellular molecular sensor called the inflammasome, which is a multiprotein complex formed by the oligomerization of proteins including NLRP3 (Nod-like receptors pyrin domain-containing 3) and ASC (Apoptosis-associated Speck-like protein containing a CARD domain). This sensor activates caspase 1, an enzyme that converts pro-interleukin 1β (pro-IL-1β) into its mature and active form, IL-1β. This molecular mechanism converts the nutritional signal into an immune response. Under physiological conditions, this acute response appears to have beneficial effects on the body. Indeed, it plays a positive role in blood glucose control by stimulating insulin secretion and glucose utilization (Dror, Nat Immunol 2017). However, in the context of chronic overeating and excessive consumption of saturated fats and simple sugars, this systemic inflammation becomes harmful, promoting adipocyte hypertrophy, insulin resistance, hepatic steatosis, and vascular damage (Hotamisligil, Nature 2017). In mice, our team recently demonstrated the existence of a postprandial inflammatory response in the central nervous system (Cansell, Glia 2021). This response occurs specifically in the hypothalamus, a brain structure involved in regulating food intake and controlling energy metabolism. It is characterized by microglial reactivity visible as early as 3 hours after the start of the postprandial phase. This postprandial microglial activation occurs after the ingestion of a high-fat meal, whereas it is rarely or never observed after the ingestion of a standard balanced meal. It is characterized by a morphological change in hypothalamic microglia, including an increase in the length of microglial processes and their branching. This gliosis is associated with increased expression of IL-1β in microglial cells. Thus, the postprandial gliosis observed 3 hours after a high-fat meal is inflammatory. Using a targeted genetic approach that allows for the ablation of the inflammasome in microglial cells, the team demonstrates that postprandial gliosis exerts a satiating effect, limiting subsequent food intake following a high-calorie, high-fat meal. Thus, microglial inflammation appears to be an additional component in the body's arsenal of adaptive homeostatic responses aimed at limiting energy intake. Our clinical project will involve translating our basic findings in mice to humans. This will involve investigating postprandial hypothalamic gliosis in the human brain following a standard meal or a high-fat meal. The initial studies will be conducted exclusively in healthy male subjects to avoid the influence of the hormonal cycle on the hypothalamic response. The impact of physiological aging on the hypothalamic microglial inflammatory response will also be taken into account.

Interventions

• Biological Blood sample
  Hormone and metabolic tests (insulin, IGF-1, leptin, blood glucose, ghrelin)
• Procedure Brain MRI without contrast, performed on an empty stomach and after a meal
  Measurement of the T1 and T2 relaxation times in the hypothalamic region
• Other Questionnaires
  Eating habits and preferences
• Other Bioelectrical impedance analysis
  Measurements of lean body mass, fat mass, body water and bone mass

Primary outcome measures

• The difference in hypothalamic MRI signal intensity between the baseline state and the postprandial state observed after a balanced meal and after a high-fat meal for each subject. [Time frame: 2 days]

Eligibility criteria

Inclusion criteria

• A person who has given oral consent
• Male
• Body Mass Index (BMI) between 18.5 and 30 kg/m²
• Age ≥ 20 years

Exclusion criteria

• A person subject to a measure of legal protection (guardianship, tutorship)
• A person subject to a judicial protective measure
• A person who is not enrolled in or eligible for a social security program
• Subject does not speak French
• Subjects with a pacemaker or any other contraindication to MRI
• Subjects with type 1 or type 2 diabetes
• Subjects with a chronic inflammatory condition
• Subjects with a neuropsychiatric condition
• Subjects taking anti-inflammatory medication or medication that affects the central nervous system
• Known hypersensitivity to foods provided during the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

France · 1 center

• Chu Dijon Bourgogne — Dijon

Identifiers

NCT: NCT07557628 · SCHNEIDER 2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗