Diminished insulin sensitivity is associated with altered brain activation to food cues and with risk for obesity – Implications for individuals born small for gestational age

Mucellini, Amanda Brondani; Miguel, Patrícia Maidana; Molle, Roberta Dalle; Rodrigues, Danitsa Marcos; Machado, Tania Diniz; Reis, Roberta Sena; Toazza, Rudineia; Salum, Giovanni Abrahão; Bortoluzzi, Andressa; Franco, Alexandre R.; Buchweitz, Augusto; Barth, Bárbara; Agranonik, Marilyn; Nassim, Marouane; Meaney, Michael J.; Manfro, Gisele Gus; Silveira, Patrícia Pelufo

doi:10.1016/j.appet.2021.105799

Cited by 5 publications

(2 citation statements)

References 116 publications

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“… 9 , 21 , 23 , 26 These metabolic and neurochemical effects are accompanied by changes in cognitive flexibility, sensitivity to reward, and poor inhibitory control. 9 , 21 , 22 , 26 , 27 The behavioral and metabolic phenotype observed in animals exposed to FR recapitulates the profile detected in humans born after exposure to prenatal adversity 28 – 48 with striking accuracy. In humans, differences in DA function associate with the increased palatable food consumption in IUGR individuals.…”

Section: Introductionmentioning

confidence: 63%

Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction

Batra

Cuesta

Alves

et al. 2023

J Dev Orig Health Dis

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Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.

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Section: Introductionmentioning

confidence: 63%

Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction

Batra

Cuesta

Alves

et al. 2023

J Dev Orig Health Dis

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“…In contrast to these results, a previous study found increased feeding behavior entropy in prenatally food‐restricted rats (Laureano et al., 2019), which corroborates findings in humans that were born small for gestational age. These individuals were less likely to choose the same snack consumed months earlier when the spatial arrangement was modified, which is indicative of a less organized food “plating” pattern (Mucellini et al., 2022). However, these apparently opposite results are understandable when we consider the important differences between these protocols.…”

Section: Discussionmentioning

confidence: 99%

The impact of poor fetal growth and chronic hyperpalatable diet exposure in adulthood on hippocampal function and feeding patterns in male rats

Mucellini,

Laureano,

Alves

et al. 2024

Developmental Psychobiology

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Poor fetal growth affects eating behavior and the mesocorticolimbic system; however, its influence on the hippocampus has been less explored. Brain insulin sensitivity has been linked to developmental plasticity in response to fetal adversity and to cognitive performance following high‐fat diet intake. We investigated whether poor fetal growth and exposure to chronic hyperpalatable food in adulthood could influence the recognition of environmental and food cues, eating behavior patterns, and hippocampal insulin signaling. At 60 days of life, we assigned male offspring from a prenatal animal model of 50% food restriction (FR) to receive either a high‐fat and ‐sugar (HFS) diet or standard chow (CON) diet. Behavioral tests were conducted at 140 days, then tissues were collected. HFS groups showed a diminished hippocampal pAkt/Akt ratio. FR‐CON and FR‐HFS groups had higher levels of suppressor of cytokine signaling 3, compared to control groups. FR groups showed increased exploration of a novel hyperpalatable food, independent of their diet, and HFS groups exhibited overall lower entropy (less random, more predictable eating behavior) when the environment changed. Poor fetal growth and chronic HFS diet in adulthood altered hippocampal insulin signaling and eating patterns, diminishing the flexibility associated with eating behavior in response to extrinsic changes in food availability in the environment.

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A mesocorticolimbic insulin receptor gene co-expression network moderates the association between early life adversity and food approach eating behaviour style in childhood

Jaramillo-Ospina,

Dalle Molle,

Patel

et al. 2025

Appetite

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Diminished insulin sensitivity is associated with altered brain activation to food cues and with risk for obesity – Implications for individuals born small for gestational age

Cited by 5 publications

References 116 publications

Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction

Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction

The impact of poor fetal growth and chronic hyperpalatable diet exposure in adulthood on hippocampal function and feeding patterns in male rats

A mesocorticolimbic insulin receptor gene co-expression network moderates the association between early life adversity and food approach eating behaviour style in childhood

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