Sanjivini Suresh

Introduction. Adverse Childhood Experiences (ACEs) refer to instances of trauma that occur before the age of 18, including exposure to violence, abuse, neglect, substance use, incarceration, etc. ACEs have been correlated with higher incidences of respiratory and heart disease, cancer, diabetes, and obesity.¹ While research on ACE-related obesity is lacking, current studies suggest that ACEs downregulate proopiomelanocortin (POMC) production from the Hypothalamic-Pituitary-Adrenal (HPA) Axis, which results in increased food intake. Methods. In the first study, researchers exposed newborn mice to either no stress, chronic stress, or chronic stress plus an antisense oligonucleotide for POMC then measured serum concentrations of HPA-associated peptides.² In the second study, researchers subjected male mice to chronic stress then assessed changes in neuronal excitability.³ In the third study, researchers mutated GABAergic POMC neurons in the arcuate nucleus of the hypothalamus (POMC^ARH) to prevent POMC production at that site then measured food intake.⁴ In the fourth study, researched inhibited the pathway between POMC^ARH and dopamine neurons in the ventral tegmental area (DA^VTA) while measuring food intake.⁵ In the last study, researchers used CRISPR/Cas9 technology to induce gain-of-function mutations into melanocortin 4 receptors (MC4R) to assess changes in food intake.⁶  Results. The first study showed that despite the absence of active stress, exposure to early life stress causes persistent suppression of Corticotropin-Releasing Hormone. Inhibiting POMC production during active stress, however, completely blunts the stress response.² The second study demonstrated that when exposed to chronic stress, the frequency of excitatory inputs to POMC neurons decrease while the action potential threshold and food intake increase.³ The third study demonstrated that restoring POMC production in previously inhibited GABAergic neurons normalizes food intake and disinhibits Neuropeptide Y (NPY) neurons in the dorsomedial hypothalamic nucleus, which normally promote in food intake.⁴ The fourth study showed that if the POMC^ARH à DA^VTA pathway is inhibited in the midst of stress, mice demonstrate increased weight and food intake.⁵ The last study found that increasing the activity of MC4R decreases weight gain and food intake in a specific-sex manner.⁶ Conclusions. These studies indicate that early life stress permanently downregulates POMC production by increasing the action potential threshold and decreasing excitatory inputs to POMC neurons, which subsequently causes disinhibition of NPY neurons and inhibition of dopamine neurons. An MC4R agonist may be able to bypass the POMC circuitry and directly stimulate MC4R, consequently decreasing food intake.⁷

1. Dempster KS, O’Leary DD, MacNeil AJ, et al. Linking the hemodynamic consequences of adverse childhood experiences to an altered HPA axis and acute stress response. Brain Behav Immun. 2021;93:254-263. doi:10.1016/j.bbi.2020.12.018.
2. Campana G, Loizzo S, Fortuna A, et al. Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice. 2021;73(1):186-195. doi:10.1007/s12020-021-02659-4.
3. Ha GE, Cheong E. Chronic Restraint Stress Decreases the Excitability of Hypothalamic POMC Neuron and Increases Food Intake. Exp Neurobiol. 2021;30(6):375-386. doi: 10.5607/en21037.
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6. Rojo D, McCarthy C, Raingo J, et al. Mouse models for V103I and I251L gain of function variants of the human MC4R display decreased adiposity but are not protected against a hypercaloric diet. Mol Metab. 2020;42:101077. doi: 10.1016/j.molmet.2020.101077.
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