Abstract
Energy homeostasis is regulated in coordinate fashion by the brain-gut axis, the homeostatic energy balance circuitry in the hypothalamus and the hedonic energy balance circuitry comprising the mesolimbcortical A10 dopamine pathway. Collectively, these systems convey and integrate information regarding nutrient status and the rewarding properties of ingested food, and formulate it into a behavioral response that attempts to balance fluctuations in consumption and food-seeking behavior. In this review we start with a functional overview of the homeostatic and hedonic energy balance circuitries; identifying the salient neural, hormonal and humoral components involved. We then delve into how the function of these circuits differs in males and females. Finally, we turn our attention to the ever-emerging roles of nociceptin/orphanin FQ (N/OFQ) and pituitary adenylate cyclase-activating polypeptide (PACAP)—two neuropeptides that have garnered increased recognition for their regulatory impact in energy homeostasis—to further probe how the imposed regulation of energy balance circuitry by these peptides is affected by sex and altered under positive (e.g., obesity) and negative (e.g., fasting) energy balance states. It is hoped that this work will impart a newfound appreciation for the intricate regulatory processes that govern energy homeostasis, as well as how recent insights into the N/OFQ and PACAP systems can be leveraged in the treatment of conditions ranging from obesity to anorexia.
Highlights
Academic Editor: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA; College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
Sex differences are abundantly present in the context of energy homeostasis and the prevalence of obesity is similar between men and women, women seem to have a greater risk of developing eating disorders and extreme obesity [121,122]
We have discovered that the endogenous release of nociceptin/orphanin FQ (N/OFQ) caused by high-frequency optogenetic stimulation of ventral tegmental area (VTA) neurons in mesencephalic slices from
Summary
The intricate balance between energy intake and expenditure, is regulated in coordinate fashion by homeostatic and hedonic neural circuits [1]. ARC POMC/CART neurons are categorized as glucoseresponsive neurons and take up glucose via a glucose transporter (GLUT2) where it metabolizes, producing ATP and thereby promoting the closure of ATP-dependent potassium (KATP ) channels to reduce the outflow of K+ , leading to the depolarization of the cell [22,23] This aligns POMC cellular excitability and firing rate in direct proportion to glucose concentrations, with satiety signaling accentuated as glucose levels rise (e.g., during or shortly following a meal) [22,23]. While for insulin, several prior studies reported inhibitory responses in POMC neurons due to activation of KATP channels, it is known that the proportion of excitatory vs inhibitory insulin-induced responses is dependent on ambient levels of protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TCPTP) activity [45,46,47] Both enzymes are expressed in ARC neurons integral to the regulation of energy balance. Appetite-promoting effects are due to its excitatory effects on NPY/AgRP and orexin neurons
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