Central nervous system regulation of organismal energy and glucose homeostasis

Myers, Martin G.; Affinati, Alison H.; Richardson, Nicole; Schwartz, Michael W.

doi:10.1038/s42255-021-00408-5

Cited by 89 publications

(68 citation statements)

References 229 publications

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“…The energy balance is controlled by the central nervous system (CNS) [ 17 , 18 , 19 , 20 ]. The master regulator is the hypothalamus, where all signals from other brain areas and from the periphery are integrated and translated into specific behavioral, autonomic, and endocrine outputs [ 17 , 18 , 19 , 21 , 22 ].…”

Section: Obesity: Epidemiology Etiopathophysiology and Early Developmentmentioning

confidence: 99%

Early Life Stress, Brain Development, and Obesity Risk: Is Oxytocin the Missing Link?

Colleluori

Galli

Severi

et al. 2022

Cells

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Obesity disease results from a dysfunctional modulation of the energy balance whose master regulator is the central nervous system. The neural circuitries involved in such function complete their maturation during early postnatal periods, when the brain is highly plastic and profoundly influenced by the environment. This phenomenon is considered as an evolutionary strategy, whereby metabolic functions are adjusted to environmental cues, such as food availability and maternal care. In this timeframe, adverse stimuli may program the body metabolism to maximize energy storage abilities to cope with hostile conditions. Consistently, the prevalence of obesity is higher among individuals who experienced early life stress (ELS). Oxytocin, a hypothalamic neurohormone, regulates the energy balance and modulates social, emotional, and eating behaviors, exerting both central and peripheral actions. Oxytocin closely cooperates with leptin in regulating energy homeostasis. Both oxytocin and leptin impact the neurodevelopment during critical periods and are affected by ELS and obesity. In this review article, we report evidence from the literature describing the effect of postnatal ELS (specifically, disorganized/inconstant maternal care) on the vulnerability to obesity with a focus on the role of oxytocin. We emphasize the existing research gaps and highlight promising directions worthy of exploration. Based on the available data, alterations in the oxytocin system may in part mediate the ELS-induced susceptibility to obesity.

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Section: Obesity: Epidemiology Etiopathophysiology and Early Developmentmentioning

confidence: 99%

Early Life Stress, Brain Development, and Obesity Risk: Is Oxytocin the Missing Link?

Colleluori

Galli

Severi

et al. 2022

Cells

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“…One mechanism monitors physiological state (i.e., protein balance or protein need state) and signals when an imbalance is present. This classic homeostatic paradigm is expressed in many systems (energy balance, sodium balance) and is typically driven by endocrine signals that act within the brain [1,2,7,8,15,[62][63][64]. Currently, the specific mechanisms mediating the long-term detection of protein balance are not clear, but recent work has implicated a variety of possibilities.…”

Section: Food Choice As An Interaction Between Short-term (Within a Meal) And Long-term (Need State) Signalsmentioning

confidence: 99%

“…For instance, energy expenditure is reduced to conserve remaining energy stores, the motivation to find and consume food is increased, and short-term satiety signals (such as gut distension) have a diminished effect, resulting in larger meals once the food is consumed. Many reviews have covered the homeostatic regulation of energy balance, and it is well accepted that a variety of hormones act as nutritional signals and engage neural circuits controlling feeding behavior and energy expenditure [1][2][3][4][5][6][7][8][9][10][11]. However, do animals only defend against energy restriction?…”

Section: Introduction: Protein As Unique Nutrient Providing Essential Amino Acidsmentioning

confidence: 99%

Protein Appetite at the Interface between Nutrient Sensing and Physiological Homeostasis

et al. 2021

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Feeding behavior is guided by multiple competing physiological needs, as animals must sense their internal nutritional state and then identify and consume foods that meet nutritional needs. Dietary protein intake is necessary to provide essential amino acids and represents a specific, distinct nutritional need. Consistent with this importance, there is a relatively strong body of literature indicating that protein intake is defended, such that animals sense the restriction of protein and adaptively alter feeding behavior to increase protein intake. Here, we argue that this matching of food consumption with physiological need requires at least two concurrent mechanisms: the first being the detection of internal nutritional need (a protein need state) and the second being the discrimination between foods with differing nutritional compositions. In this review, we outline various mechanisms that could mediate the sensing of need state and the discrimination between protein-rich and protein-poor foods. Finally, we briefly describe how the interaction of these mechanisms might allow an animal to self-select between a complex array of foods to meet nutritional needs and adaptively respond to changes in either the external environment or internal physiological state.

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“…Therefore, the studies of microglial alterations to body weight showed the expected parallel effects on glycemic parameters (Dorfman et al, 2017; Gao et al, 2017; Kim et al, 2019; Niraula et al, 2021; Wang et al, 2020). However, CNS regulation of energy balance and systemic glycemia occurs via distinct pathways (Myers et al, 2021), raising the untested possibility of direct body weight-independent effects of microglial activation on glucose homeostasis. Here, using cell-specific models combined with approaches to account for or eliminate weight differences between groups, we reveal an unexpected benefit of microglial activation to improve glucose tolerance through a TNFα-dependent mechanism.…”

Section: Introductionmentioning

confidence: 99%

Microglial inflammatory activation paradoxically improves glucose tolerance during diet-induced obesity

Douglass

Valdearcos

Ness

et al. 2022

Preprint

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Hypothalamic gliosis associated with high fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain, and is therefore presumed to promote obesity-associated consequences such as glucose intolerance as well. Nevertheless, the body weight-independent contribution of microglial activation to glucose regulation has not been determined. Here we show that reducing microglial NF-κB signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance and insulin resistance despite reducing body weight and adiposity. This effect was associated with reduced activity of hypothalamic glucose sensing neurons. Conversely, a genetic approach to increase microglial inflammatory activity improved glucose tolerance independently of diet in lean rodents. To avoid confounding effects due to chronic alterations to microglial signaling pathways from dietary or genetic interventions, we developed an inducible model of microglial activation using DREADD-based chemogenetics. Gq-coupled GPCR activation rapidly increased microglial calcium levels, cytokine gene expression, and morphological hallmarks of inflammatory activation. In both lean and obese rodents, chemogenetic microglial activation caused a marked improvement in glucose tolerance along with increased activation of hypothalamic glucose sensing neurons, effects abrogated by central blockade of TNFα signaling. Thus, while diet-induced microglial activation promotes weight gain, it may also serve an adaptive function—to prevent the deterioration of glucose tolerance associated with obesity, an important consideration for immune-modulating metabolic therapies.

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Central nervous system regulation of organismal energy and glucose homeostasis

Cited by 89 publications

References 229 publications

Early Life Stress, Brain Development, and Obesity Risk: Is Oxytocin the Missing Link?

Early Life Stress, Brain Development, and Obesity Risk: Is Oxytocin the Missing Link?

Protein Appetite at the Interface between Nutrient Sensing and Physiological Homeostasis

Microglial inflammatory activation paradoxically improves glucose tolerance during diet-induced obesity

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