Much research has pointed to how an unhealthy diet correlates to obesity, but has not explored how diet can bring about neurological changes in the brain.
A recent Yale study has discovered that high-fat diets contribute to irregularities in the hypothalamus region of the brain, which regulates body weight homeostasis and metabolism.
Led by Sabrina Diano, the Richard Sackler Family Professor of Cellular & Molecular Physiology and professor of neuroscience and comparative medicine, the study evaluated how the consumption of a high-fat diet – specifically diets that include high amounts of fats and carbohydrates – stimulates hypothalamic inflammation, a physiological response to obesity and malnutrition.
The researchers reaffirmed that inflammation occurs in the hypothalamus as early as three days after consumption of a high-fat diet, even before the body begins to display signs of obesity.
“We were intrigued by the fact that these are very fast changes that occur even before the body weight changes, and we wanted to understand the underlying cellular mechanism,” said Diano who is also a member of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.
The researchers observed hypothalamic inflammation in animals on a high fat diet and discovered that changes in physical structure were occurring among the microglial cells of animals.
These cells act as the first line of defense in the central nervous system that regulate inflammation.
Diano’s lab found that the activation of the microglia was due to changes in their mitochondria, organelles that help our bodies derive energy from the food we consume.
The mitochondria were substantially smaller in the animals on a high-fat diet.
The mitochondria’s change in size was due to a protein, Uncoupling Protein 2 (UCP2), which regulates the mitochondria’s energy utilization, affecting the hypothalamus’ control of energy and glucose homeostasis.
The UCP2-mediated activation of microglia affected neurons in the brain that, when receiving an inflammatory signal due to the high fat diet, stimulated the animals in the high-fat diet group to eat more and become obese.
However, when this mechanism was blocked by removing the UCP2 protein from microglia, animals exposed to a high fat diet ate less and were resistant to gain weight.
The study not only illustrates how high-fat diets affect us physically, but conveys how an unhealthy diet can alter our food intake neurologically.
“There are specific brain mechanisms that get activated when we expose ourselves to specific type of foods.
This is a mechanism that may be important from an evolutionary point of view. However, when food rich in fat and carbs is constantly available it is detrimental.”
Diano’s long-standing goal is to understand the physiological mechanisms that regulate how much food we consume, and she continues to perform research on how activated microglia can affect various diseases in the brain, including Alzheimer’s disease, a neurological disorder that is associated with changes in the brain’s microglial cells and has been shown to have higher incidence among obese individuals.
The study was published in Cell Metabolism.
Over half of the US population is classified as overweight and a full third is classified as obese (1).
The number of obese people has increased steadily over the last 30 years (2).
This increase in obesity has coincided with an increase in co-morbidities, such as type 2 diabetes, cardiovascular disease, stroke, and hypothalamic disorders, including reproductive disorders that cause infertility (3–6).
Deleterious effects of obesity on fertility include irregularities in menstrual cycles, abnormalities in the oocyte development, anovulation, and increased risk of miscarriages in women (3); and inferior sperm quality, reduced sperm quantity, and lower testosterone levels in men (7).
The hypothalamus in the basal forebrain controls feeding and satiety, thermoregulation, thirst, circadian rhythms, metabolism, and mammalian reproduction.
In the control of reproduction, the hypothalamic decapeptide gonadotropin-releasing hormone (GnRH) is the final brain output that regulates expression and secretion of gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gonadotropes (16), which in turn stimulate steroidogenesis and gametogenesis in the gonads (17, 18).
In the rodent hypothalamus, the majority of GnRH cell bodies are scattered in the preoptic area surrounding organum vasculosum laminae terminalis (OVLT), while secretion occurs at the terminals in the median eminence (ME). Both OVLT and ME are circumventricular areas with a leaky blood-brain barrier, whereby hypothalamic neurons perceive changes in the circulation and neuropeptides reach the portal circulation (19).
GnRH secretion is synchronized by upstream regulatory neuronal populations (20).
Metabolic stimuli and energy status, such as anorexia nervosa, excessive exercise, malnutrition, and obesity are also integrated with reproductive function at the level of the hypothalamus (11–13, 15, 26, 27).
Obesity is characterized by chronic inflammation, in addition to changes in metabolic markers (31).
Increased adiposity elicits an increase in inflammatory cytokines in the circulation (32, 33), such as: tumor necrosis factor (TNFα), and interleukins, IL-1β, IL-6 (34), primarily due to macrophage infiltration to adipose tissue and their subsequent activation.
Inflammatory cytokines have been demonstrated to negatively affect reproductive function (35).
Influence of acute inflammation on reproduction was an area of intense investigation and these studies determined that LPS or cytokine administration in the brain ventricle reduces gonadotropin levels, diminishes GnRH neuropeptide release and represses GnRH and LH gene expression (36–38).
As opposed to the acute, high level of inflammatory cytokines used in previous studies, obesity elicits low grade, chronic inflammation and we investigated its effects on reproduction via GnRH neurons.
To analyze the effects of obesity-induced inflammation on reproductive function we used diet-induced obese (DIO) mice. Significant strain differences were observed in response to high-fat diet (HFD) and A/J, FVB/NJ and BALB/cJ strains are resistant to DIO, while DBA/2J and C57BL/6J gain weight (39–41).
The C57BL/6J mouse is a particularly faithful model of the human metabolic syndrome because it develops obesity, hyperinsulinemia, hyperglycemia, and hypertension, when allowed ad libitum access to a HFD (42, 43).
Herein, we demonstrate profound sex differences in response to HFD. Specifically, C57BL/6J male mice exhibit neuroinflammation, with a resultant decrease in the number of synaptic spines on GnRH neurons and reduction in GnRH mRNA levels.
On the other hand, female mice are resistant to neuroendocrine and inflammatory changes, and this protection is independent of ovarian hormones.
Together, our data implicate sex-specific effects in obesity-induced neuroinflammation with functional consequences on GnRH neurons.
More information: Jung Dae Kim et al. Microglial UCP2 Mediates Inflammation and Obesity Induced by High-Fat Feeding, Cell Metabolism (2019). DOI: 10.1016/j.cmet.2019.08.010
Journal information: Cell Metabolism
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