Obesity-programmed mice are rescued by early genetic intervention

Abstract

Obesity is a chronic metabolic disorder affecting half a billion people worldwide. Major difficulties in managing obesity are the cessation of continued weight loss in patients after an initial period of responsiveness and rebound to pretreatment weight. It is conceivable that chronic weight gain unrelated to physiological needs induces an allostatic regulatory state that defends a supranormal adipose mass despite its maladaptive consequences. To challenge this hypothesis, we generated a reversible genetic mouse model of early-onset hyperphagia and severe obesity by selectively blocking the expression of the proopiomelanocortin gene (Pomc) in hypothalamic neurons. Eutopic reactivation of central POMC transmission at different stages of overweight progression normalized or greatly reduced food intake in these obesity-programmed mice. Hypothalamic Pomc rescue also attenuated comorbidities such as hyperglycemia, hyperinsulinemia, and hepatic steatosis and normalized locomotor activity. However, effectiveness of treatment to normalize body weight and adiposity declined progressively as the level of obesity at the time of Pomc induction increased. Thus, our study using a novel reversible monogenic obesity model reveals the critical importance of early intervention for the prevention of subsequent allostatic overload that auto-perpetuates obesity.

Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

“…6H). The phenotypes observed in PomcIsl1KO mice are reminiscent of those previously reported in Pomc-deficient mice (4,35). Chronic and excessive accumulation of adipose tissue may lead to a generalized health disorder known as metabolic syndrome, which includes the development of a fatty liver and type II diabetes.…”

“…POMC neurons sense leptin, insulin and glucose levels, and receive multiple synaptic contacts which, together, orchestrate neuronal activity and determine the pattern of melanocortins release (2,3). The physiological relevance of the central melanocortin system can be readily appreciated in hypothalamic Pomc-deficient mice, which are hyperphagic and display early onset severe obesity (4). In addition, humans carrying biallelic null POMC variants are also severely obese (5).…”

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

“…Number 9 September 2016 strain resulted in obesity without affecting lean mass (16), most Pomc mutants generated on 129 and/or C57/BL6 backgrounds showed both obesity and increased lean mass (19,63). Since lean mass is the principal site of glucose disposal, caution is warranted when interpreting glucose metabolic data in these mutants, especially if the assays were performed based on the body weight (64).…”

17α‐estradiol acts through hypothalamic pro‐opiomelanocortin expressing neurons to reduce feeding behavior

“…Deletion of nPE2, nPE1, or insertion of a transcription‐blocking neo selection cassette into the vicinity of the two hypothalamic neuronal Pomc enhancers reduces hypothalamic Pomc expression to ~80%, ~30%, or ~2% of wild‐type controls, respectively (Lam et al, 2015). A reduction in hypothalamic Pomc expression at or below ~30% of wild‐type controls in these mice results in a functional loss of Pomc ‐mediated regulation of body mass (Bumaschny et al., 2012; Lam et al., 2015; Zhan et al., 2013). Therefore, we hypothesized that if 17α‐E2 were to act selectively by increasing hypothalamic Pomc expression, the treatment effects on body mass and food intake would be disrupted in mutant mice lacking nPE1 ( Pomc Δ1 ) or those containing the Pomc transcription‐blocking neo selection cassette ( Pomc neo ).…”