Behavioral Feeding Circuit: Dietary Fat-Induced Effects of Inflammatory Mediators in the Hypothalamus

Abstract

Excessive dietary fat intake has extensive impacts on several physiological systems and can lead to metabolic and nonmetabolic disease. In animal models of ingestion, exposure to a high fat diet during pregnancy predisposes offspring to increase intake of dietary fat and causes increase in weight gain that can lead to obesity, and without intervention, these physiological and behavioral consequences can persist for several generations. The hypothalamus is a region of the brain that responds to physiological hunger and fullness and contains orexigenic neuropeptide systems that have long been associated with dietary fat intake. The past fifteen years of research show that prenatal exposure to a high fat diet increases neurogenesis of these neuropeptide systems in offspring brain and are correlated to behavioral changes that induce a pro-consummatory and obesogenic phenotype. Current research has uncovered several potential molecular mechanisms by which excessive dietary fat alters the hypothalamus and involve dietary fatty acids, the immune system, gut microbiota, and transcriptional and epigenetic changes. This review will examine the current knowledge of dietary fat-associated changes in the hypothalamus and the potential pathways involved in modifying the development of orexigenic peptide neurons that lead to changes in ingestive behavior, with a special emphasis on inflammation by chemokines.

Maternal Low-Grade Chronic Inflammation and Intrauterine Programming of Health and Disease

“…The ending point of these two opposite situations is a paradoxical common prenatal metabolic programming of insulin sensitive tissues (i.e., pancreas, adipocytes, and skeletal muscle), which further explains the common later phenotype of metabolic syndrome in adulthood. In this context, diet-induced animal models have clarified that maternal obesity is associated with the following changes in the offspring: 1. adipose tissue modifications: increased sex-dependent adipogenesis (greater in males) with adipocyte hypertrophy, local inflammation enhanced PPAR- γ expression (obesogenic gene strictly related to lipid metabolism, cytokine production, and adipogenesis), reduced β 2- and β 3-adrenoreceptor expression and increased cytokine mRNA expression [ 79 , 83 , 93 ]; 2. central modifications: programmed hyperphagia (greater in male progeny), independent on postnatal nutrition, as a result of altered hypothalamic energy sensors and epigenetic responses, leading to altered development, neuronal abnormal differentiation, and appetite dysregulation [ 86 , 88 , 96 ]; 3. liver modifications: hepatic inflammation, steatosis, and fibrosis, leading to increased risk of nonalcoholic fatty liver disease, increased triglyceride accumulation and lipogenesis, enhanced proinflammatory cytokine and serum insulin expression, and premature gluconeogenic gene activation with impaired carbohydrate metabolism [ 80 , 82 , 89 ]; 4. skeletal muscle modifications: enhanced macrophage infiltration, increased inflammatory properties with upregulation of PPAR- γ , TLR2–4 , NF- κ B , and TNF α gene expression, intramuscular adipogenesis with adipocyte hypertrophy and hyperplasia, and reduced insulin receptor mRNA expression, together resulting in decreased muscular insulin sensitivity and functional impairment [ 77 , 81 , 87 , 90 , 97 ].…”

Central Neurocircuits Regulating Food Intake in Response to Gut Inputs—Preclinical Evidence

“…At the NTS–DMV brainstem synapse, for example, there is a attenuation of the developmental switch in GABA A receptors subunit composition that alters the channel kinetics and subsequently increases inhibitory drive from the NTS that is associated with decreased gastric motility [ 139 ], although the long-term effects of this developmental delay on feeding behavior needs to be determined. Hypothalamic-DVC neurocircuits are also altered by maternal HFD exposure [ 140 ]. Elevated levels of orexigenic neuropeptides are present after maternal HFD that resembles the phenotype observed following adult HFD exposure [ 138 ], possibly due to transcriptional changes at the neuronal level [ 141 , 142 ].…”

Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment

“…This research has resulted in a proposed "two hit" hypothesis for the development of PCOS phenotypes (43,45). The "first hit" involves developmental programming of inherited susceptibility genes and the "second hit" arises due to lifestyle and environmental influences in childhood, adolescence and adulthood (41,106).…”