DOI: https://doi.org/10.53350/pjmhs22168407 ORIGINAL ARTICLE P J M H S Vol. 16, No. 08, August 2022 407 The Role of Fibroblast Growth Factor 21 as an Endocrine Regulator of Lipid Metabolism: From Progression to Pathophysiology and Physiology RAISA NAZ 1 , AINA KHURSHID 2 , AMBAR SHUAIB 3 , MALIK SHANDAR KHAN 4 , MUHAMMAD SHOAIB 5 , AQSA ASLAM 6 , INAM-U-LLAH 7 , SUDHAIR ABBAS BANGASH 8 , IRFAN ULLAH 9 1 Department of Physiology, Ayub Medical College Abbottabad 2 Department of Biochemistry, Multan Medical and Dental College, Multan. 3 Department of Physiology, Pak International Medical College, Peshawar, Pakistan 4 Department of Physiology, Khyber Girls Medical College, Peshawar. 5 Department of Biochemistry, Gajju khan medical college, Swabi. 6 Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University Multan. 7 Department of Food Science, the University of Haripur, KPK, Pakistan 8 Faculty of Life Science, Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar 8 Department of Life Sciences, School of Science, University of Management and Technology, Lahore, Pakistan Corresponding authors: Ambar Shuaib, Email: ambarshuaib50@gmail.com & Muhammad Shoaib, Email: shoaaiiib@gmail.com) ABSTRACT Objective: The primary aim of this research was to study the molecular history of fibroblast growth factor 21 (FGF21) as well as its physiological and pathological functions. Study Design: Observational study Place and Duration: This study was carried out at Hayatabad Medical Complex from December 2021 to April 2022 Methods: There were 77 patients of non-alcoholic fatty disease had age 20-65 years were presented in this study. After obtaining informed written consent details demographics were recorded. Diseases of all the patients were recorded and their relation with the FGF21 levels was observed. SPSS 23.0 was used to analyze all data. Mean standard deviation was use for categorical variables. Results: There were 42 (54.5%) males and 35 (45.5%) females among all cases. Mean age of the patients was 40.11±8.74 years and had mean BMI 27.8±11.34 kg/m 2 . Majority of the patients 31 (40.3%) had diabetes mellitus, 24 (31.2%) cases had renal failure, 20 (25.97%) cases had cardiovascular disease, mitochondrial disease in 17 (22.1%) cases, energy metabolism disorder in 15 (19.5%), lipid metabolism disorder in 13 (16.9%) and frequency of stroke was 9 (11.7%). We found significantly increased volume of FGF21 among diabetic obese cases which were resistant to insulin with p value <0.005. Conclusion: Pathophysiological functions, potential risk factors, and diagnostic biomarkers for endocrine FGFs in adult metabolic and genetic diseases are all supported by the available evidence. Pharmaceutical research is being conducted on endocrine FGFs. These results provide insight on the pathological and physiological functions of endocrine FGFs and offer new insights into the diagnosis and treatment of metabolic disorders. Keywords: FGF21, Lipid Metabolism, Pathaphysiology, Outcomes INTRODUCTION In the first stage of isolating the prototypical fgfs factors (FGFs), also known as mitogens for cultured fibroblasts, FGF1 and FGF2 were obtained from brain and pituitary-derived fibroblasts [1, 2]. In both humans and mice, the Fgf1-Fgf23 gene cluster is a member of the same historical family as a whole. Because the mouse Fgf15 gene and the human Fgf19 gene are orthologous to one another, we shall refer to these genes jointly as Fgf15/19 throughout this research. Proteins with a similarity of 13-71% between mouse and human FGFs contain 150-300 amino acids in their structure. FGFs are signalling molecules that play a wide variety of roles in both development and metabolism. Their core regions each contain 120 amino acids, and they share between 30 and 60 percent of their amino acids with one another. The Fgf gene family has undergone little change through time and is expressed in a wide variety of embryonic and adult tissues [3]. Based on its mode of action, FGFs are divided into three groups: extracts of c., intracrine, or neuroendocrine [4]. Specialization, cell growth, and migration are all crucial developmental processes that rely on FGFs as secreted local biologically different signalling molecules. To accomplish this, they communicate with the cell surface FGF receptors (FGFRs) [5]. There is a connection between intracrine function and the signalling molecules known as FGFs 11–14 (FGFs). They are involved in postnatal neuronal functioning in a manner that is independent of FGFR [6]. Endocrine Related (FGF15/19, FGF21, and Clarification) are proteins that are secreted and have the ability to influence biological effects via FGFRs. FGFs that have an endocrine activity can act over long distances and are engaged in the metabolism of the body after birth [7,8]. The liver, the pancreas, white adipose tissues, and muscle are only some of the many tissues that express the growth factor FGF21 [9]. The phenotypes of viable and fertile FGF21 knockout mice demonstrate that the protein enhances lipid metabolism in white adipose tissue during eating but inhibits it while the animals are fasting [9]. Evidence from FGF21 mutant rats fed a ketogenic diet reveals that FGF21 promotes to adaptation but lowers insulin sensitivity in fatty tissue [10]. According to research carried out with FGF21 knockout mice [11], many of the systemic side effects of FGF21 on energy homeostasis and insulin sensitivity inside the skeletal muscle and liver are mediated by adiponectin. [citation needed] In addition to playing a crucial part in the process of preserving glucose homeostasis, glucagon has a regulatory role in the metabolism of lipids and promotes weight loss. The level of FGF21 expression in the livers of mice is increased when the glucagon receptor is activated. This growth factor may play a function in the glucagon-regulated conversion of carbohydrate, energy, and lipids, according to data obtained from mice lacking FGF21 [12]. Similarly, FGF21 knockout animals, which have normal blood sugar levels, show insulin resistance. This is linked to increased pancreas proliferation or endogenous insulin as a form of compensation. FGF21 may regulate beta-cell proliferation and endogenous insulin production [13]. This likely takes place thru the modulation of hgh signalling. Pancreatic islets with a mutation that knocks out FGF21 are more sensitive to the actions of growth hormone, which helps explain their resistance. Endoplasmic membrane (ER) stress and the evolution of the condition are linked to a variety of diseases and conditions, including obesity and diabetes. ER stress causes an increase in the expression of FGF21 in the liver. Animals with a mutation in FGF21 that causes increased ER stress also develop an accumulation of lipids in the liver, which points to a function for FGF21 in the adaptation to ER stress. In mice lacking FGF21, there is an increase in both the relative heart mass and symptoms of dilatation. When the heart is now under stress, it responds by cells secrete huge amounts of