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While the laws of thermodynamics dictate that obesity is caused by an imbalance between caloric intake and energy expenditure, the drivers of each of these may be laid down before the manifestation of the phenotype. We present evidence over the last half-century that suggests that the temporospatial evolution of obesity from intrauterine life and beyond is, in part, due to the conditioning of physiological processes at critical developmental periods that results in maladaptive responses to obesogenic exposures later in life. We begin the review by introducing studies that describe an association between perinatal factors and later risk of obesity. After a brief discussion of the pathogenesis of obesity, including the systemic regulation of appetite, adiposity, and basal metabolic rate, we delve into the mechanics of how intrauterine, postnatal and early childhood metabolic environments may contribute to adult obesity risk through the process of metabolic conditioning. Finally, we detail the specific epigenetic pathways identified both in preclinical and clinical studies that synergistically \u201cprogram\u201d obesity.<\/jats:p>","DOI":"10.3389\/fendo.2022.1032491","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T04:38:35Z","timestamp":1666067915000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":45,"title":["The metabolic conditioning of obesity: A review of the pathogenesis of obesity and the epigenetic pathways that \u201cprogram\u201d obesity from conception"],"prefix":"10.3389","volume":"13","author":[{"given":"Ananthi","family":"Rajamoorthi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"LeDuc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidhu V.","family":"Thaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"B1","unstructured":"Obesity and overweight: World health organization2021"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acdb.2016.10.006","article-title":"The development of body image and weight bias in childhood","volume":"52","author":"Paxton","year":"2017","journal-title":"Adv Child Dev Behav"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s12098-017-2539-2","article-title":"Psychological aspects of obesity in children and adolescents","volume":"85","author":"Sagar","year":"2018","journal-title":"Indian J Pediatr"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0803514","article-title":"Early adiposity rebound: Causes and consequences for obesity in children and adults","author":"Rolland-Cachera","year":"2006","journal-title":"Int J Obes (Lond)."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.12.050","article-title":"Blaming the brain for obesity: Integration of hedonic and homeostatic mechanisms","volume":"152","author":"Berthoud","year":"2017","journal-title":"Gastroenterology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"977","DOI":"10.3390\/nu13030977","article-title":"Ghrelin and glucagon-like peptide-1: A gut-brain axis battle for food reward","volume":"3","author":"Decarie-Spain","year":"2021","journal-title":"Nutrients"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1105816","article-title":"Long-term persistence of hormonal adaptations to weight loss","volume":"365","author":"Sumithran","year":"2011","journal-title":"N. 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