Defense of Elevated Body Weight Setpoint in Diet-Induced Obese Rats on Low Energy Diet Is Mediated by Loss of Melanocortin Sensitivity in the Paraventricular Hypothalamic Nucleus

Abstract

Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks’ refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint.

A history of opioid exposure in females increases the risk of metabolic disorders in their future male offspring

“…This effect was not observed under FSD conditions. Thus, findings suggest diminished melanocortin tone within the PVN of MORF1 males, and further support the notion that even under the CD conditions, these animals are primed for a metabolically adverse phenotype 42. Within the VTA, no differences in α-MSH were observed, demonstrating region-specific modifications in POMC-derived neuropeptide distribution.…”

Low-Carbohydrate Diets in the Management of Obesity and Type 2 Diabetes: A Review from Clinicians Using the Approach in Practice

“…A recent trial demonstrated that carbohydrate restriction is more beneficial for patients with higher insulin levels [44]. This is consistent with insulin [57,58] influencing the so-called "set point" [59] of eating behavior and body weight regulation, in the same way that efficacious interventions such as drug therapy [60] and surgery [61] do but which calorie restriction in isolation can't [62]. Ketosis has been shown to attenuate the increases in ghrelin and appetite that occur with dietary restriction [63] and there is growing interest in the role of therapeutic ketosis in weight loss interventions [64].…”

Long-Term Changes in Weight in Patients With Severe and Complicated Obesity After Completion of a Milk-Based Meal Replacement Programme

“…The reason for weight regain after successful weight loss is complex and likely multifactorial, with factors such as hypothalamic-mediated weight homeostasis, environmental and psychological variables, frequency of interactions with health care professionals, participation in exercise, and underlying genetic pre-dispositions of the patients themselves to obesity all playing potential roles ( 20 – 23 ). Studies in rats have confirmed a strong and persistent neuro-humoral response to caloric restriction that drives weight regain once ad libitum food intake is restored ( 24 ). These physiological counter-regulatory mechanisms to preserve energy balance are driven by genetic and epigenetic factors which lead to an imprinted obesogenic “memory” that prevents weight loss maintenance ( 25 ).…”