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Maternal nutrition exerts profound and lasting effects on infant development, with implications extending beyond somatic growth to long-term brain function and metabolic health. For example, newborns from mothers with obesity or diabetes exhibit increased susceptibility to metabolic disorders, including insulin resistance (IR) and type 2 diabetes (T2D), often emerging in childhood or adolescence. While genetic inheritance contributes to this intergenerational risk, early-life nutritional exposures are increasingly recognized as primary drivers of persistent metabolic programming. Among key classes of nutrients, branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—have emerged as potent modulators of metabolic health in human adults. Elevated circulating BCAAs are among the most accurate predictors of future insulin resistance (IR) and T2D, with a two-fold increase in serum levels conferring a 2.5-fold risk of diabetes onset within 6–10 years. This elevation can directly cause organ toxicity, exacerbating metabolic deficits in a feed-forward loop. However, the extent to which maternal BCAA overnutrition during gestation and lactation impacts offspring metabolic programming and predisposes to dysfunction remains unclear.

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Downstream interaction by glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide agonism is required for synergistic effects on body weight

Claire H. Feetham, Minrong Ai, Isabella Culotta, Alessia Costa, ... Simon M. Luckman

Downstream interaction by glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide agonism is required for synergistic effects on body weight

 

Objectives

Dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor agonists (GLP1RA and GIPRA, respectively) synergise to reduce body weight. Though this synergy depends on receptors within the brain, where and how this occurs is unclear.

Methods

We employed a combination of neuroanatomical approaches in the mouse to investigate access of the dual GLP1RA/GIPRA, tirzepatide, and study the central targets engaged by single agonist, dual agonist and combined agonist treatments. Genetic manipulations were then used to further investigate the functional significance of specific brain regions and distinct neuronal subtypes.

Results

We recorded penetration of fluorescently labelled tirzepatide limited mainly to circumventricular organs and confirmed the importance both GLP1R and GIPR in the dorsal vagal complex for the actions of systemically administered agonists. Receptor expression indicates GIPRA alone activates a distinct population of GABA neurons in the area postrema directly, but also neurotensin neurons in the central amygdala (NtsCeA) indirectly. Disabling NtsCeA neurons selectively reduces the synergistic effect of dual GLP1R/GIPR agonist administration on body weight.

Conclusions

As with selective GLP1RA, the actions of dual GLP1RA/GIPA appear to be dependent on the dorsal vagal complex for their action, probably most importantly by gaining access through the area postrema. Downstream targets include the central amygdala where signals following dual receptor agonism interact. Specifically, NtsCeA neurons are required for the full synergistic effect of dual receptor agonism on body weight.

 

 

Articles in Press

Downstream interaction by glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide agonism is required for synergistic effects on body weight

Claire H. Feetham, Minrong Ai, Isabella Culotta, Alessia Costa, ... Simon M. Luckman

Downstream interaction by glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide agonism is required for synergistic effects on body weight

 

Objectives

Dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor agonists (GLP1RA and GIPRA, respectively) synergise to reduce body weight. Though this synergy depends on receptors within the brain, where and how this occurs is unclear.

Methods

We employed a combination of neuroanatomical approaches in the mouse to investigate access of the dual GLP1RA/GIPRA, tirzepatide, and study the central targets engaged by single agonist, dual agonist and combined agonist treatments. Genetic manipulations were then used to further investigate the functional significance of specific brain regions and distinct neuronal subtypes.

Results

We recorded penetration of fluorescently labelled tirzepatide limited mainly to circumventricular organs and confirmed the importance both GLP1R and GIPR in the dorsal vagal complex for the actions of systemically administered agonists. Receptor expression indicates GIPRA alone activates a distinct population of GABA neurons in the area postrema directly, but also neurotensin neurons in the central amygdala (NtsCeA) indirectly. Disabling NtsCeA neurons selectively reduces the synergistic effect of dual GLP1R/GIPR agonist administration on body weight.

Conclusions

As with selective GLP1RA, the actions of dual GLP1RA/GIPA appear to be dependent on the dorsal vagal complex for their action, probably most importantly by gaining access through the area postrema. Downstream targets include the central amygdala where signals following dual receptor agonism interact. Specifically, NtsCeA neurons are required for the full synergistic effect of dual receptor agonism on body weight.

 

 

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13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026                                                                                                                             

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You are what you eat

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