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It could be, for example, an adapting nerve system

Tirzepatide produced 33.9% fat mass loss in SURMOUNT-1

Pernicious anaemia, an autoimmune loss of intrinsic factor, is the classic one

Increased absolute concentrations of intracellular NAD + links with activation of NAD + -dependent histone deacetylases (e.g., sirtuins) that also mediate epigenetic regulation of gene expression[40] and adipocyte physiology.[45] Similarly, increased intracellular concentrations of SAM, a universal substrate for SAM-dependent histone methyltransferases, could have profound influence on cellular epigenetic modifications, including transcriptional regulation and the expression of genes that regulate adipogenesis and/or thermogenesis promoting browning of adipocytes (e.g., PPAR, PRDM16, UCP1, Wnt).[4648] NNMT protein expression is relatively lower in the murine brown adipose tissue (BAT) compared to the WAT [37] and nnmt (a WAT-selective gene [49, 50]) gene expression has been reported to be lower in the BAT of HFD fed mice compared to normal chow-fed mice.[49] Furthermore, NNMT activity is significantly higher in the white fat compared to brown adipose tissue and the other organs (e.g., liver, lungs) in DIO mice.[16] Hence, treatment with an NNMT inhibitor in DIO mice may less likely impact BAT or other tissue NNMT activity, but could be speculated to modulate thermogenic/adipogenic genes in the WAT