The debate on the relative contributions of presumptive etiologic factors in the development
of obesity is becoming increasingly speculative, insular, and partisan. As the global
prevalence of obesity continues to rise, the sheer volume of unfounded conjecture
threatens to obscure well-established evidence. We posit that the failure to distinguish
between causal factors and mere statistical associations engendered the proliferation
of misleading and demonstrably false research programs and failed public health initiatives.
Nevertheless, scientific progress necessitates the elimination of unsupported speculation
via critical examinations of contrary evidence. Thus, the purpose of this review is
to present a concise survey of potentially falsifying evidence for the major presumptive
etiologic factors inclusive of 'diet', 'genes', physical activity, and non-physiologic
factors from the social sciences. Herein, we advance two 'Fundamental Questions of
Obesity' that provide a conceptually clear but challenging constraint on conjecture.
First, why would an individual (i.e., human or non-human animal) habitually consume
more calories than s/he expends? And second, why would the excess calories be stored
predominantly as 'fat' rather than as lean tissue? We posit that the conceptual constraint
presented by these questions in concert with the parallel trends in body-mass, adiposity,
and metabolic diseases in both human and non-human mammals offer a unique opportunity
to refute the oversimplification, causal reductionism, and unrestrained speculation
that impede progress. We conclude this review with an attempt at consilience and present
two novel paradigms, the 'Metabolic Tipping Point' and the 'Maternal Resources Hypothesis',
that offer interdisciplinary explanatory narratives on the etiology of obesity and
metabolic diseases across mammalian species.